Histone posttranslational modifications: Potential role in diagnosis, prognosis, and therapeutics of cancer

CHAPTER

Histone posttranslational modifications: Potential role in diagnosis, prognosis, and therapeutics of cancer

13

Asmita Sharda⁎,†, Ramchandra V. Amnekar⁎,†, Abhiram Natu⁎,†, Sukanya⁎,†, Sanjay Gupta⁎,† Epigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India⁎ Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India†

1 ­Introduction Cancer is a one of the major cause of mortality, and its individual and collective impact is substantial. Genetic aberrations are responsible yet not the sole contributors for cancer development. It is epigenetic dysregulation, coupled with genetic alterations that contribute to the pathophysiology of cancer [1]. Epigenetic regulation comprises a variety of mechanisms including DNA methylation, histone modifications, histone variant and isoform incorporation, nucleosome remodeling, and RNA interference mechanisms. Synergistic hierarchies between these mechanism and combinations of pathways dictate alterations in chromatin structure as they occur during various cellular processes. Due to alterations in the epigenome, cancer cells often bypass important checkpoints and gain control of essential cellular processes like DNA repair, metabolism, and cell death [2]. This ultimately leads to rampant cellular proliferation, thereby outnumbering normal cells. Therefore, translational emphasis is on using novel, nongenetic approaches to target the reversible epigenetic changes for cancer treatment. Various novel targets, in terms of chromatin-modifying enzymes, have come up to be promising targets for “epidrug” therapy. However, more rigorous studies are required to expand our understanding of cancer and improvise in the areas of diagnosis, prognosis, and therapeutics. A number of global histone PTM studies have highlighted their prognostic utility, suggesting a fundamental association between global histone modification levels and tumor aggressiveness, overall/disease-free survival and metastasis regardless of cancer tissue of origin [3]. Since epigenetics is now a vastly expanding field, our group has created a freely available database, HIstome (http://www.actrec.gov.in/histome/), covering information about histone proteins, PTMs, and modifying enzymes. In the present review, we aim to provide comprehensive information about reports that explore histone PTMs and modifiers for their diagnostic and prognostic utility against cancer. Additionally, we explore various avenues where histone PTMs can be utilized in the clinics for better cancer management.

Prognostic Epigenetics. https://doi.org/10.1016/B978-0-12-814259-2.00014-5 © 2019 Elsevier Inc. All rights reserved.

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Chapter 13  Clinical relevance of histone modifications

2 ­Histone posttranslational modification in cancer Aberrant histone modifications such as phosphorylation, N-terminal acetylation, methylation, sumoylation, ubiquitination, citrullination, and poly ADP-ribosylation are known to play a key role in the pathogenesis of cancer. A range of modifiers/enzymes responsible for different modifications like histone acetyltransferases (HATs), histone deacetylases (HDACs), histone lysine methyltransferases (KMTs), and histone lysine demethylases (KDMs) are known to change in different cancers. Recent studies have shown that levels of circulating histones and nucleosomes are increased in cancer, which suggest that histones could be possibly suitable as biomarkers and therapeutic targets. These details of histone modifications and modifiers are dealt with in more detail in the next sections and summarized in Fig. 1.

2.1 ­Histone acetylation Histone acetylation is one of the earliest identified histone PTM. This seminal discovery paved the way for extensive exploration of the functional and regulatory contribution of PTMs on histones [4]. Acetylation occurs on ε-amino nitrogen of lysine residues present at the N-terminal tail of histones. Addition of the negatively charged acetyl group on basic histones causes decondensation of chromatin due to weakened DNA-histone electrostatic interaction. Chromatin relaxation (on cis-regulatory regions like enhancers and promoters) also facilitates access to underlying DNA and enables processes such as transcription [5]. Interestingly, acetylation of H4K16 is one of the predominant PTMs that regulate global chromatin architecture by preventing the formation of 30-nm compact chromatin fiber [6]. Acetylation of histones at H3K9, H3K14, H3K18, H3K27, and H4K16 position has been associated with release of paused RNA polymerase II for transcription of immediate early genes like c-fos, c-jun, c-myc, and cyclinD [7]. Thus, histone acetylation is crucial for gene expression, replication, DNA damage repair processes, gene reprogramming, and development-related processes, and any deregulation could result in cancer [8]. In 2005, an important report was published, suggesting the loss of histone H4K16ac and H4K20me3 to be a hallmark of several human cancers like breast, gastric, colon, lymphoma, and leukemia [9]. The downregulation or genomic loss of acetyltransferase hMOF leads to low levels of H4K16ac, as reported in breast cancer, gastric cancer, and medulloblastoma. This decrease in hMOF levels correlate with poor survival of medulloblastoma patients and also distant metastasis in case of gastric cancer [10, 11]. A retrospective study carried out suggests that gastric cancer patients with high H4K16ac and H3K9ac showed better survival than those with high methylation. However, groups with codominant expression of acetylation and methylation showed intermediate survival [12]. Low H3K9ac levels in gastric and ovarian cancers are also linked to poor prognosis [13]. Similarly, high H3K9ac levels correlate with prolonged disease-free survival in non–small cell lung carcinoma [14]. This possibly suggests a direct correlation between H3K9ac and better prognosis. Such correlations (along with other significant alterations) should be assessed and validated in future studies. Another histone PTM, H3K18ac, which is important for mitotic fidelity [15], has been under scrutiny for its prognostic significance in several cancers. In lung and kidney cancers, low H3K18ac levels act as an independent prognostic marker and corroborates with poor survival [16]. Low levels of H3K18ac predict better prognosis for overall survival of patients having node-negative resectable pancreatic tumors. The patients having high H3K18ac were observed to have a better response toward 5-fluorouracil treatment [17]. In contrast to these

FIG. 1 Histone modifications and modifiers altered in human cancers. Individual core histones, H2A, H2B, H3, and H4 with their N-and C-terminal tail, different histone PTMs, and their respective modifiers have been depicted in this figure. Different modifications on specific residues are represented in different colors. An “arrow” indicates “writer” (enzyme that adds the PTM) enzyme, whereas “erasers” (enzymes that remove the PTM) are depicted as a “stop arrow.” Modifying enzyme(s) not yet identified are depicted as “?.” HDAC is depicted as "#."

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reports, high H3K18ac levels significantly correlate with tumor stage, poor prognosis, and survival in pancreatic cancer [18]. However, in esophageal squamous cell carcinoma [19], H3K18ac levels correlate with tumor grade and survival in stages I and II, whereas in prostate cancer [20], it correlates only with tumor grade. Thus, depending on the tumor tissue type, the histone PTM levels can have different prognostic outcomes. In case of colon cancer, H3K27ac was found to be upregulated [21]. The histone PTM H4K12ac, which is found on newly synthesized histones [22], was found to correlate positively with tumor grade in case of prostate cancer [20]. Similar observation was made in pancreatic cancer, where high H4K12ac levels positively correlated with tumor grade, advanced stage (III and IV), and poor survival of patients. It was also found to be an independent prognostic factor for overall survival [18]. Table 1 summarizes the studies demonstrating the correlation between histone acetylation levels and various clinical parameters. Histone acetylation and deacetylation are a well-orchestrated event mediated by histone acetyltransferases (HAT) and histone deacetylases/sirtuins (HDACs/SIRTs), respectively. Based on the catalytic domain, HATs can be classified into three families—p300/CBP, Gcn5 N-acetyltransferases or GNATs, and the MYST family. All HATs function as a part of multiprotein complexes like SWI–SNF and SAGA [24]. HDACs are Zn+2-dependent enzymes, whereas sirtuins are NAD+-dependent enzymes, catalyzing the removal of acetyl group from histones and nonhistone proteins. HDACs are classified into four classes. These are class I (HDAC1–HDAC3 and HDAC8) and class II (HDAC4–HDAC7, HDAC9, and HDAC10). Class II is subdivided into IIa (HDACs 4, 5, 7, and 9) and IIb (HDACs 6 and 10). Class III comprises NAD-dependent Sirtuins (SIRT1–SIRT8) and class IV has only HDAC11. Of these, class I and class II b is localized in nucleus and cytoplasm, respectively. Class II a, class III, and class IV have localization in both nucleus and cytoplasm [25]. Reports that demonstrate the importance of histone acetyl modifiers in cancer are summarized in Table 2.

2.2 ­Histone methylation Histone methylation occurs on arginine (R) or lysine (K) residues of histones, utilizing S-adenosyl methionine (SAM) as methyl donor. These residues have the propensity to undergo mono-, di-, or trimethylation, which may be symmetric or asymmetric in case of arginine methylation. Histone methylation has the potential to impact gene expression, by either activation or repression, depending on the genomic location, number of methyl groups added, and the histone residue undergoing methylation. For example, trimethylation at H3K9 and H3K27 position is associated with transcription repression, whereas monomethylation at this position is associated with active transcription. In case of H3K4, H3K36, and H3K79, both mono- and trimethylation are associated with active transcription [37]. Several studies have suggested that histone methylation marks can serve in diagnosis and prognosis of cancer [38]. The trimethylation on H3K27 and its modifying enzyme (enhancer of zeste homolog 2 [EZH2]) associate with transcription repression and are deregulated in cancer. H3K27me3 acts as an independent prognostic factor and, in combination with EZH2, could predict lymph node metastasis in case of gastric cancer [39]. In case of esophageal squamous cell carcinoma, low expression of H3K27me3 correlates with better survival of stage I and II esophageal squamous cell carcinoma patients [19]. High levels of H3K27me3 in colorectal cancer were associated with poor overall survival, histological grade, and initial metastasis [40]. In childhood posterior fossa (PF) ependymomas, histological grade

Table 1  Histone acetylation levels and their clinical correlation Histone modification

1.

H4K16ac

2.

H3K9ac

3.

H3K18ac

Cancer

Levels

Correlation

Reference

Breast Non–small cell lung cancer Non–small cell lung cancer Ovarian

Low Low Low Low

[23] [14] [14] [13]

Lung and kidney Pancreatic

Low Low High High

Tumor siz, grade, and vascular invasion Tumor recurrence, distant metastasis, pTNM stage, Tumor recurrence, distant metastasis Inverse relation with grade of tumor; low expression in serous cystadenocarcinomas Survival outcome Positive correlation with 5-fluorouracil response High tumor grade and poor prognosis Tumor grade H3K4me2 and H3K18ac predict a higher risk of prostate cancer recurrence. Positive correlation with tumor grade – Tumor grade Tumor grade, advanced stage (III and IV), and poor survival of patients

[20]

Esophageal squamous cell carcinoma Prostate

4. 5.

H3K27ac H4K12ac

Colorectal Prostate Pancreatic

High

High High High

NSCLC, Non–small cell lung cancer; ESCC, esophageal squamous cell carcinoma.

[16] [17, 18] [19]

[21] [20] [18]

2 ­ Histone posttranslational modification in cancer

S. no

355

356

Table 2  Histone acetyl modifier levels and their clinic-pathological correlation Modifier

Cancer

Levels

Correlation

Reference

1.

P300

2. 3.

CBP hMOF

4.

HDAC1

HCC Breast cancer Colon Small cell lung cancer Small cell lung cancer Breast Medulloblastoma Gastric Colorectal

High High High High High Loss Loss High High High High

Poor survival, tumor size, differentiation Histological grade, clinical stage, recurrence Poor survival, poorly differentiated tumors OS, DFS, and risk of recurrence OS, DFS, and risk of recurrence Poor survival Poor survival Poor survival Depth of tumor invasion and stage Tumor stage, distant metastasis, proliferation Advanced tumor stage, poor differentiation, and tumor aggressiveness Proliferation Gleason score, proliferation(Ki67) Proliferation(Ki67), Disease-specific survival Nodal status, grade Better survival Tumor stage, distant metastasis Gleason score, proliferation(Ki67), PSA-free relapse Proliferation(Ki67), Poor survival, disease-specific survival

[26] [27] [28] [29] [29] [11] [11] [30] [31, 32]

5.

HDAC2

Pancreatic Prostate Ovarian–endometrial

High High High in serous subtype

Gastric Pancreatic Colorectal Prostate

High High High High

Ovarian–endometrial

High(more in high grade serous subtype) High High High in serous subtype

6.

HDAC3

Colorectal Prostate Ovarian–endometrial

7.

HDAC4

Pancreatic

High

OS, Overall survival; DFS, disease-free survival; SCLC, small cell lung cancer.

Tumor stage, distant metastasis, proliferation Proliferation(Ki67) Proliferation(Ki67), Poor survival, disease\-specific survival The absence of organ metastasis

[33] [34] [35] [36] [30] [34] [32] [35] [36]

[32] [35] [36] [34]

Chapter 13  Clinical relevance of histone modifications

No

2 ­ Histone posttranslational modification in cancer

357

does not predict reliable prognosis. H3K27M mutations present in posterior fossa ependymomas are comparable with PF–ve ependymomas, in context of reduced H3K27me3 global levels. H3K27me3 was found to be a biomarker of poor prognosis and thus could help in understanding invasive tumors in posterior fossa ependymomas [41]. An interesting report revealed that H3K27me3 follows an age-­ dependent prognosis pattern in colorectal cancer. Relapse-free progression was associated with a decrease in level of H3K27me3 with advancing age, whereas relapsed cases exhibited an increase in this mark with time [42]. The mono-, di-, or trimethylation at H3K9 is associated with heterochromatin formation and is related to transcription repression. High level of H3K9me3 was found to be an independent prognostic marker for poor survival in gastric adenocarcinoma [12] and also positively correlate with lymph node metastasis in colorectal cancer [43]. Analysis of both H3K4me2 and H3K9me2 could better predict survival of pancreatic adenocarcinoma patients, thus putting the prognostic utility of more than one PTM to use [17]. Levels of H3K9me2, but not other methylations (H3K4me2 or H3K27me3), displayed a sequential increase during progression of colorectal cancer. Levels ranged from least in normal glandular cells to adenocarcinoma having maximum H3K9me2 levels. This study suggests that progressive increase in H3K9me2 could be in an important event during the process of colorectal cancer development [44]. Previously, histone methylation marks H3K9me3 and H4K20me3 were identified in circulating nucleosomes, thereby suggesting histone methylation marks as potential ­serum-based biomarkers. It was observed that H3K27me3 and H4K20me3 were detectable in plasma of colorectal cancer patients by ELISA, at levels lower than healthy controls. This interesting observation provides a starting point to explore the potential of liquid biopsy-based histone PTM detection [45]. As highlighted previously, the loss of both H4K16ac and H4K20me3 is considered to be a hallmark of several cancers [9]. Likewise, the loss of H4K20Me3 and its decreased expression was observed in both lung cancer and preneoplastic lesions of squamous cell carcinoma [46, 47]. H3K4 trimethylation is associated with active gene promoters [48]. In breast cancer, low level of H3K4me2, H4K20me3, and H4R3me2 correlate with poor prognosis in basal carcinoma subtype and HER2 positive tumor type [23]. Alternatively, high levels of H3K4me3 is associated with reduced overall survival in early stage hepatocellular carcinoma patients [49]. In case of colorectal carcinoma, low H3K4me3 and high H3K9me3 and H4K20me3 were associated with good prognosis and diseasefree survival. Thus, a combination of histone marks (rather than single methylation mark) lead to better stratification of patients [50]. H3K36me3 was reported as downregulated in colorectal cancer patients [51]. A report also suggests that patients with H3K36me3 negative renal cell carcinoma had poor survival and higher risk of disease-associated death [52]. Table 3 summarizes the studies demonstrating the correlation between histone methylation levels with various clinical parameters. Methylation on specific lysine residues of histones is carried out by lysine methyltransferases like Set1, MLL1, MLL2, MLL3, and MLL4 [54, 55]. PRMT enzymes catalyze the transfer of methyl group onto arginine residues of histones. The modifications mediated by these methyl transferase enzyme complexes mediate various fundamental biological processes [56]. Table 4 summarizes several studies related to different histone methyltransferases and demethylases and cancer.

2.3 ­Histone phosphorylation Histone phosphorylation has been reported to regulate critical cellular processes such as transcription and DNA repair and also associates with condensed state of chromatin.

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Table 3  Levels of histone methylation in different cancers and association with clinical parameters S. no.

Histone PTM

Cancer

Level

Correlation

Reference

1. 2.

H3K27me3 H3K27me3

Gastric cancer Colorectal Cancer

High High

[39] [40]

3.

H3K4me2

High

4. 5.

H4K20me3 H3K9me3

Luminal like breast cancer Squamous cell carcinoma Gastric adenocarcinoma

Lymph node metastasis Better stratification of patients Tumor biomarker phenotype

6.

H3K4me2

7.

H3K36me3

Pancreatic adenocarcinoma Renal cell carcinoma

Low High

Low Low

Disease progression Tumor stage, lymphovascular invasion, and cancer recurrence T and N stage and histological grade Higher risk of disease-related deaths

[23] [46] [12]

[17] [53]

Table 4  Histone methyltransferases and demethylase levels and their clinical correlation S. no.

Modifying enzyme

Cancer

Level

Correlation

Reference

1.

SETD 7

Prostate cancer

High

[57]

2.

EZH1–2

Low Low

3.

NSD2

4.

PRMT 1,5,6

Renal cell carcinoma Colorectal cancer Colorectal cancer Breast cancer

Digital rectal examination, preoperative PSA, pT stage, lymph node metastasis T stage and grading Lymph node metastasis, Histological type

5.

MLL MLL 3,4 PRDM 9 SETD 1A,1B Glp1 G9a

6.

Low Low

Hepatocellular carcinoma

High

Renal cell carcinoma

Low

Lymph node metastasis, histological type Histone modification status, tumor biomarker phenotype Tumor differentiation, TNM stage, vascular invasion

T stage and grading

[58, 59]

[59] [23] [49]

[58]

In response to DNA damage, rapid and reversible phosphorylation of H2A variant H2AX occur the Ser-139 residue [60]. This phosphorylated form of H2AX, known as γH2AX, spreads up to megabases both upstream and downstream of the DNA break site and acts to recruit various proteins to initiate the DNA repair process [61, 62]. Interestingly, H2AX−/− mice, though viable, exhibit radiation sensitivity and enhanced tumor susceptibility. Therefore, induction or persistence of γH2AX is strongly ­associated

2 ­ Histone posttranslational modification in cancer

359

with genomic instability [63]. Thus, assessment of γH2AX levels has various clinical applications such as testing environmental genotoxicity of compounds, biodosimeter for radiation exposure, drug pharmacodynamics, and testing efficacy of novel chemotherapeutic agents. Various studies point toward efficacy of γH2AX as a predictor for cancer prognosis, diagnosis, and treatment efficacy, as summarized [64]. Interestingly, majority of these reports, unequivocally point to the strong correlation between high levels of γH2AX with clinical parameters such as advanced stage tumor and reduced overall survival. Various chemotherapeutic drugs and radiotherapy induce γH2AX; therefore this mark could serve as a good indicator for treatment efficacy. The studies that highlight γH2AX as an independent prognostic marker are summarized in the Table 5. Depending on the cell cycle phase and genomic localization, H3 phosphorylation is generally associated with chromatin condensation/decondensation and transcriptionally active state [71–73]. H3S10P and H3S28P are two of the most extensively studied PTMs. H3S10 and S28 have various kinases (Msk1/Msk2, Pim1, Rsk2, IKKα, and aurora kinase B) and phosphorylate in a contextdependent manner [74]. In the context of cellular transformation, phosphorylation of histone H3 has been considered indispensible [75]. It has been demonstrated that during cellular transformation, constitutively active v-src leads to persistent H3S10P levels. Also, it has previously been reported that Msk1 phosphorylates H3S10 during cellular transformation mediated by EGF and TPA [76]. Nasopharyngeal carcinoma induced by Epstein–Barr virus latent membrane protein-1 (LMP-1) exhibits higher H3S10P levels compared with chronic nasopharyngitis and strongly correlates with the expression of LMP-1. In the same study, overexpression of H3S10A mutant decreased cell proliferation; the mechanism being LMP-1 mediated increased Msk1 kinase activity [77]. Additionally, our group has also reported an increase in levels of H3S10P in gastric cancer tissues compared with

Table 5  Clinical correlation of γH2AX levels with various cancers S. no.

Histone PTM

Cancer

Levels

Correlation

Reference

1.

γH2AX

High

γH2AX

3.

γH2AX

Non–small cell lung cancer

4.

γH2AX

Preneoplastic lesions

[68]

5.

γH2AX

High

Poor overall survival

[69]

6.

γH2AX

Hepatocellular carcinoma Oral squamous cell carcinoma Gastric cancer

High γH2AX Low γH2AX-p53 High

Tumor localization, stage, alcohol consumption, and smoking Poor distant metastasis-free survival, overall survival, tumor stage, and perineurial invasion Short overall survival Better overall survival

[65]

2.

Laryngeal cancer Colorectal Cancer

High

Tumor location, differentiation, invasiveness, lymph node metastasis Helicobacter pylori positive intestinal metaplasia and dysplasia

[70]

High

[66]

[67]

NSCLC, Non–small cell lung cancer; HCC, hepatocellular carcinoma; OSCC, oral squamous cell carcinoma; OS, overall survival.

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Chapter 13  Clinical relevance of histone modifications

disease-free surgically resected cut margins. Further, high H3S10P correlates strongly with poor survival. Additionally, upon investigation of the mechanism, high H3S10P correlates with phospho-P38 MAPK/Msk1-mediated increase of H3S10P [78]. Phosphohistone H3 (pHH3) is considered to be a mitotic mark, and also cancer cells are associated with higher mitotic activity. Assessment of pre- and posttreatment pHH3 levels may indicate treatment effectiveness and also helps in grading of multiple tumor types [79]. A retrospective study revealed higher expression of H3S10P than H3S28P in ovarian cancer and melanoma, thus highlighting the prognostic potential of pHH3 [80]. High pHH3 has also been reported to be an independent prognostic factor predicting poorly differentiated state of esophageal squamous cell carcinoma [81]. A recent study demonstrated higher levels of pHH3 in TNBCs compared with luminal breast cancer based on mitotic activity index (MAI), as quantified by pHH3 staining. Through MAI quantification, the study also demonstrates the effectiveness of epirubicin- and taxotere-based neoadjuvant chemotherapy on highly proliferative TNBCs and luminal breast cancer [82]. High levels of other histone H3 PTMs such as H3T6, H3S10, and H3Y41 correlate with poor prognosis of glioblastoma multiforme (treated with temozolomide and irradiation). This was attributed to high expression of the respective kinases, PKC, aurora kinase B, and JAK2 [83]. An alteration in global levels of histone phosphorylation is a direct indication of deregulation in the levels, expression or activity of their respective kinases, or phosphatases [84]. Table 6 summarizes the levels and prognostic significance of various histone kinases and phosphatase.

2.4 ­Histone ubiquitylation Histone H2A was the first histone identified to be monoubiquitylated. Histone ubiquitylation, occurring on lysine residues, is altered in several cancers. In case of parathyroid tumor, H2B monoubiquitylation decreases after the loss of CDC73, which is one of the important binding partner of RNF20 and RNF40 E3 ubiquitin protein ligases [93]. Decrease of H2B monoubiquitylation in lung adenocarcinoma Table 6  Histone kinase and phosphatase levels and their correlation with clinical parameters S. no.

Enzyme

Cancer

Levels

Correlation

Reference

1.

ATM (ataxia telangiectasia mutated)

High Low Low

MKP-1/ DUSP-1 (MAP kinase phosphatase 1/ dual specificity phosphatase 1)

3.

MSK1 (mitogenspecific protein kinase 1)

Poor DFS and OS Distant metastasis, reduced DFS, and cancer-specific survival Reduced survival Better survival. Better disease-free survival rate Estrogen receptor positivity, recurrence, poor survival, and tumor stage Shorter overall survival Higher tumor grade

[85–87]

2.

Colorectal cancer Sporadic breast cancer Hormone negative breast cancer Non–small cell lung cancer Hepatocellular carcinoma Breast cancer Colorectal cancer Breast cancer

OS, Overall survival; DFS, disease-free survival.

High High Low

High Low

[88–90]

[91, 92]

2 ­ Histone posttranslational modification in cancer

361

has been associated with poor differentiation, malignancy, and shorter survival [94]. Additionally, decreased levels of RNF20/RNF40 and H2Bub1 are associated with increased inflammation in colorectal cancer [95]. Similarly, progressive H2B monoubiquitylation decrease, and ubiquitin-specific protease enzyme 22 (USP22) increase was observed in a stage-wise manner in colon cancer [96]. Decreased ubH2B is associated with lower survival of malignant gastric cancer patients [97]. Thus, ubH2B could be a promising biomarker in several cancer but requires in depth investigation.

2.5 ­Histone citrullination Histone citrullination occurs by enzymatic conversion of arginine residue to citrulline. This leads to chromatin relaxation and enables activation of transcription. H3 citrullination play a central role in release of chromatin from neutrophil extracellular traps (NETs), which have been shown to promote tumor progression and metastasis. In pancreatic ductal carcinoma patients, citrullinated H3 was shown to be increased because of the formation of NETs [98]. It was also observed that that increase in the plasma H3 citrullination correlated with advanced stage cancer patients in multiple cancers [99]. Patients with monoclonal gammopathy of undetermined significance and multiple myeloma exhibit H3R26Ci in bone marrow mesenchymal stem cell population [100]. Also, increased H3 citrullination was observed in castration-resistant prostate cancer [101].

2.6 ­Histone ribosylation Ribosylation on histone occurs by transfer of ribose from ADP-ribose to polar residues on histones. This modification is carried out by poly ADP-ribosyltransferases also known as PARPs. Addition of ribose moiety results in increase in negative charge on histone protein, thus helping in opening of chromatin. Histone H3 at S10 and S28 position undergo PARylation in response to DNA damage. In case of hepatocellular carcinoma, hepatitis B virus X protein abrogates the activity of PARP1 by interacting with SIRT6 in HCC patients leading to decrease in PARylation at site of DNA damage [102].

2.7 ­Histone sumoylation Histone sumoylation is termed as addition of small ubiquitin-like modifier (SUMO) proteins onto histone protein. In case of breast cancer, low expression of SUMO-specific protease 7 (SENP7L) has been significantly correlated with overall survival of breast cancer patients [103]. A summary is presented in Table 7. Histone ubiquitylation is the process of addition of single ubiquitin moiety to lysine residues of histone, carried out by ubiquitin ligases. Major class of ubiquitin ligase is RING finger E3 ligase. Monoubiquitylation can be removed by deubiquitinases. There are five classes of this enzyme out of which 1–4 are cysteine peptidases and class 5 is zinc metallo-isopeptidase. Citrullination of histone is carried out by protein arginine deiminases (PADs) that convert arginine to citrulline. The enzymatic reaction results in the hydrolysis of guanidinium side chains of arginine residues to form citrulline and ammonia. There are five types of PAD in humans, namely, PAD1, PAD2, PAD3, PAD4, and PAD6. Poly ADP-ribosylation is carried out by poly (ADP-ribose) polymerase (PARP). Nicotinamide adenine dinucleotide (NAD) acts as donor for transfer of ADP-ribose group to the lysine residue. Contrary, poly (ADP-ribose) glycohydrolase can deribosylate histone proteins. Sumoylation is an addition of small ubiquitin-like modifier onto the protein. There are four isoforms of SUMO, namely, SUMO-1,

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Chapter 13  Clinical relevance of histone modifications

Table 7  Levels of histone modifications, ubiquitylation, citrullination, ribosylation, sumoylation, and their clinical correlation S. no

Modification

Cancer

Expression/ levels

1.

H3 citrullination

Multiple cancer

Increase

2.

H3 citrullination

Pancreatic ductal carcinoma

Increase

3.

H3R26Ci

Increase

4. 5. 6.

Ribosylation uH2B uH2B

7.

uH2B

8.

uH2B

Multiple myeloma HCC Parathyroid Lung adenocarcinoma Colorectal cancer Colon cancer

Decrease

9.

uH2B

Gastric cancer

Decrease

Decrease Decrease Decrease Decrease

Correlation

Reference

Neutrophil activation, inflammation Formation of NETs via autophagy-mediated pathway Increase in IL-6 production Increase in DNA damage – Malignancy and poor survival Inflammation

[99]

Differential abundance in progressive stages Malignancy and poor survival

[98]

[100] [102] [93] [94] [95] [96] [97]

Table 8  Levels of histone-modifying enzymes for ubiquitylation, citrullination, ribosylation, sumoylation, and their clinical correlation Sr. no

Modifier

Cancer

Expression/levels

Correlation

Reference

1.

PADI2

Prostate cancer

Increase

[101]

2. 3. 4. 5.

PADI4 RNF20/RNF40 RNF20/RNF40 USP22

Multiple cancer Parathyroid Colorectal cancer Colon cancer

Increase Decrease Decrease Increases

Castration resistance Malignancy – Inflammation Disease progression

[104] [93] [95] [96]

SUMO-2, SUMO-3, and SUMO-4. Addition of SUMO group leads to increase in mass of protein by 12 kDa. SUMO-proteases are responsible for removing the modification (HIstome [http://www.actrec. gov.in/histome/]). The histone modifier levels are summarized Table 8.

3 ­Future perspectives and limitations for clinical intervention The success of any therapy or disease prevention depends on how early the disease is diagnosed and biological factors or factors that help to monitor the efficacy of treatment. This makes study of ­biomarkers specific to cancer imperative [105]. As summarized earlier, several global histone PTM

3 ­ Future perspectives and limitations for clinical intervention

363

studies have highlighted their prognostic utility, suggesting a fundamental association between global histone modification levels and modifiers with tumor aggressiveness, overall/disease-free survival and metastasis regardless of cancer tissue of origin [106]. The reversible and dynamic nature of epigenetic modifications strongly encouraged scientists, clinicians, and pharmaceutical industries to develop epigenetic biomarkers as therapeutic targets in cancer diagnosis and treatment. However, the complexity of epigenetic pathways, including the interplay of different epigenetic mechanisms in regulating gene transcription and genetic mutations in epigenetic regulators, needs to be addressed before we can fully apply our current understanding to the clinical field. However, due to extensive interindividual heterogeneity of the cancer epigenome, it becomes difficult to generalize the prognostic or diagnostic outcome of any epigenetic change. Therefore, the observations have to undergo rigorous statistical and clinical validation before pronouncing histone PTM alterations as valuable clinical tools. The following are few points that highlight how histone PTMs, along with systematic studies, may facilitate in utilizing the existing knowledge as valuable tool for better clinical outcome. 1. Adjunct to histopathological analysis: Based on histopathology, it is sometimes difficult to identify the origin of secondary malignancies. The currently used markers like Ki67, CEA, and PSA serves as predictive factors [107]. Global histone PTM alterations are tissue specific and are result of altered levels of their modifying enzymes, pathways, and metabolic perturbations [108]. Histone PTMs, like the loss of H4K16ac, is well reported to be altered in cancers of breast, stomach, lung, and lymphoma [9]. Thus, in a complex hospital setting and health center without tertiary care, histone PTM analysis can mitigate the need for different markers for prognosis of various cancers. The organ-specific histone PTMs and modifying enzymes that are up- and downregulated are depicted in Fig. 2. They can be utilized for designing a detection chip to predict the origin of tumor or as an organ-specific epigenetic signature. Thus, levels of specific histone PTMs in combination can serve as predictive markers, supplementing histopathological analysis. 2. Tumor subtypes classification: Histone PTMs can be used to differentiate between tumor subtypes. This has been well demonstrated in case of renal cell carcinoma where upregulated H3K4me2/3 was found to be specific for a papillary RCC and oncocytoma [109]. Similarly, high histone acetylation and methylation levels (H3K9ac, H4K16ac, and H3K4me2/H3K4me3) were found to be associated with well-differentiated and luminal type class, while poor prognostic classes of basal and HER-2 strongly correlated with the low histone marks cluster [23]. 3. Defining R0 resection margin: During surgery, the credibility of histological examination to define a true cut margin is contentious considering the high locoregional recurrence observed. Despite complete resection of the primary tumor, a high rate of locorecurrence is observed, suggesting the presence of residual tumor cells. These histologically normal but genetically/epigenetically, early transformed populations of cells demonstrate the concept of field cancerization [110]. Therefore, molecular investigations are required to identify the true pathological nature of the resected margins. Our group has shown the utility of H3S10P as a potential molecular marker for predicting prognosis of R0-resected gastric cancer patients using their histopathologically confirmed negative resection margins [78]. Another report suggests that discrimination of PCA and nonmalignant prostate tissue can be made with high specificity (>91%) and sensitively (>78%) and sensitivity based on H3Ac and H3K9Me2 [57]. 4. Patient stratification: The search for epigenetic biomarkers that can advise clinicians of probable prognosis, offer the most useful treatment, and serve as predictive biomarkers during the course of epidrug therapy is of significant interest while decreasing excessive morbidity of the

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FIG. 2 Organ-specific histone PTMs and modifying enzymes altered in cancer. Various histone PTMs and modifying enzymes have been reported to be altered in various cancers, which have been illustrated in this figure. PTMs and enzymes colored in green are upregulated, whereas those in red are downregulated.

patient. Questions still persist about their impact and applicability; thus, their clinical application has been limited. Patients with the same tumor stage and grade exhibit different therapeutic responses. Thus, there is a need of molecular biomarkers that could break the heterogeneity into targetable subtypes. In case of prostate cancer, hormone refractory prostate cancer patients were found to have high levels of H3K4me1, H3K4me2, and H3K4me3. Thus, these marks can stratify patients for androgen-based hormone therapy [57]. Similarly, levels of chromatin modifiers (like HDAC1 levels) can be used to stratify patients that could respond to neoadjuvant therapy [111]. 5. Utility of epigenetic drugs in cancer management: Histone PTM-based epigenetic changes are reversible in nature; therefore, direct inhibitors can be utilized toward the particular

4 ­ Conclusion

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PTM-modifying enzyme. Epidrug therapy has now been envisaged as new arsenal for therapy either alone or in combination; for example, DNMT and HDAC inhibitors are two FDA approved treatments for cancers. Levels of histone PTMs or chromatin-modifying enzymes can be further explored to identify patients that can benefit from epidrug-based adjuvant therapy [112]. Further, “epidrugs” against altered chromatin modifiers depicted in Fig. 2 can be used for potential therapeutics.

4 ­Conclusion The pathogenesis of cancer follows the three stages of initiation, promotion, and progression [113]. However, cancer tissues are composed of a heterogeneous cluster of cells with cellular epigenetic heterogeneity and different functional potentials. Analysis of histone modifications and modifiers in primary cancer tissues has now revealed a new layer of heterogeneity with significant influence on properties like proliferation, metastasis, and drug resistance [1, 106]. Further, work is needed to unravel the importance of PTMs occurring at the same residue with contrasting functions in different or same tumor tissues. Numerous novel epigenetic targets have also been identified with vast potential in epigenetic-specific therapy in combination with the existing chemo- and radiotherapies to provide reduction in drug/radiation dosage to decrease the side-effects and also reversal of the drug-resistant tumors to improve the patients’ quality of life. The stratification of patients on the basis of epigenetic alterations will be helpful in defining the better clinical outcome of epidrug therapy independently or in combination with existing therapies (Fig. 3). With thoughtful preclinical and clinical study design, we are poised to fully promote epigenetic therapy to provide meaningful clinical and better survival benefit to cancer patients.

FIG. 3 Epigenetic heterogeneity in a population can be subgrouped into categories for better clinical outcome. Epigenetic diversity in patient population is now an established fact. Analysis of various histone PTMs or modifying enzymes in clinical samples such as serum or biopsy may help in identifying patients with similar epigenetic profiles, which may help in stratification of patients into subgroups. This may be clinically helpful for predicting prognosis of patients as well enhancing effectiveness of epidrug-based therapy. This strategy has been illustrated in this figure.

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­Acknowledgment The authors would like to thank all students of Gupta lab for the critical reading of the manuscript. The work carried out by Gupta lab alumni was helpful in writing the manuscript.

­Funding AS is supported by UGC and DBT. RA and AN are supported by ACTREC fellowship, and S is supported by CSIR for her fellowship.

­Author contributions SG contributed to the conception, design, manuscript writing, and editing. AS, RA, AN, and S wrote the manuscript. AS, AN, and S prepared the figures. The article was critically read by all authors and approved for publication. Asmita Sharda, Ramchandra V. Amnekar, Abhiram Natu, and Sukanya contributed equally to this manuscript.

­Competing interests Authors declare that they have no competing interests.

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