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AUTS2 is a potential therapeutic target for pancreatic cancer patients with liver metastases
Medical Hypotheses 85 (2015) 203–206
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
AUTS2 is a potential therapeutic target for pancreatic cancer patients with liver metastases q Yong Han a,b, Guo-Qing Ru a, Xiaozhou Mou b, Hui-ju Wang b, Yingyu Ma b, Xiang-Lei He a, Zhilong Yan c, Dongsheng Huang b,c,⇑ a b c
Department of Pathology, Zhejiang Provincial People’s Hospital, Hangzhou 310014, Zhejiang, PR China Clinical Research Institute, Zhejiang Provincial People’s Hospital, Hangzhou 310014, PR China Department of General Surgery, Zhejiang Provincial People’s Hospital, Hangzhou 310014, Zhejiang, PR China
a r t i c l e
i n f o
Article history: Received 30 December 2014 Accepted 26 April 2015
a b s t r a c t Liver metastasis is a common event at the advanced stage of pancreatic malignancies. Identification of effective therapeutic targets is crucial for the management of pancreatic cancer patients with liver metastases. In this study, we show that (A) AUTS2 is overexpressed in liver metastases of pancreatic cancer and could be a biomarker for defining cancer subtypes. (B) AUTS2 expression is positively correlated with Docetaxel resistance, TGF-beta pathway activation, HEDGEHOG and WNT signaling pathway. (C) By building an AUTS2 centered protein–drug interaction network, we show that AUTS2 might promote chemotherapeutic resistance and metastasis by exerting its effect on epithelial–mesenchymal transition and WNT signaling pathway. (D) Five drugs that could down regulate the expression of AUTS2 were also suggested. These drugs might help in the treatment of pancreatic cancer patients at the stage of liver metastasis. In summary, our results indicate that AUTS2 is a candidate biomarker for defining liver metastasis of pancreatic cancer and directing personalized therapies. Ó 2015 Elsevier Ltd. All rights reserved.
Introduction Liver metastasis is the most common event at the advanced stage of pancreatic cancer. However, mechanisms underlying this process has not yet been well understood. The Autism susceptibility candidate 2 (AUTS2) is crucial in neurodevelopment and is a candidate gene for numerous neurological disorders such as autism spectrum disorders [1], intellectual disability [2,3] and developmental delay [4,5]. Literatures also show that this gene is also associated with acute lymphoblastic leukemia [6], alcoholism [7,8] and schizophrenia [9]. Lately, Kei et al. shows that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development. Loss-of-function and rescue experiments demonstrate that cytoplasmic AUTS2-Rac1 pathway is required for cortical neuronal migration and neuritogenesis in the developing brain [10]. In addition, a very recent paper published in Nature suggested that as a component of PRC1-AUTS2 complex, CK2 (CSNK2A1) neutralizes PRC1 repressive activity, whereas q Source of support: This study was supported by the Key Social Development Project of Major Science and Technology (No. 2011C13036-1). ⇑ Corresponding author at: Department of General Surgery, Zhejiang Provincial People’s Hospital, Hangzhou 30014, Zhejiang Province, PR China. Tel.: +86 0571 87666666; fax: +86 0571 85335800. E-mail address: [email protected] (D. Huang).
http://dx.doi.org/10.1016/j.mehy.2015.04.029 0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.
AUTS2-mediated recruitment of P300 (EP300) leads to gene activation [11]. Since RAC1, EP300 and CSNK2A1 play important roles in the process of metastasis among various cancer types [12–14], we assume that AUTS2 might contribute to liver metastasis of pancreatic cancer. Hypothesis AUTS2 plays critical roles in pancreatic cancer progression and is a novel therapeutic target for pancreatic cancer patients with liver metastases. Evaluation of hypothesis Expression pattern of AUTS2 in different cell lines, animal models and human samples To explore the correlation between AUTS2 and pancreatic cancer progression, several datasets were obtained from Gene Expression Omnibus (GEO) [15]. Analysis results show that AUTS2 expression is continually down regulated in the mouse pancreas development on consecutive embryo days from e12.5 to e16.5 (Fig. 1A), which indicates that AUTS2 overexpression is an early event of pancreas development. However, there is no
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Fig. 1. (A) AUTS2 expression levels in mouse dorsal pancreata on consecutive embryo days from e12.5 to e16.5. All others were compared with group e12.5. (B) Expression of AUTS2 in 45 matching pairs of pancreatic tumors and adjacent non-tumor tissues (P = 0.44). (C) AUTS2 expression in six pancreatic cancer cell lines. BxPC3, MIApaca-2, Mpanc 96 and Panc-1 were established from primary tumors, while CFPAC1 and L3.6pl were from liver metastases. (D) Expression of AUTS2 in tissues from normal main pancreatic duct, IPMA, IPMC and invasive cancer originating in IPMN. Statistical significance was determined by paired/unpaired, two-tailed Student’s t test. All the data was displayed as means ± s.e.m. ⁄P 6 0.05, ⁄⁄P 6 0.01, ⁄⁄⁄P 6 0.001. Datasets were extracted from the Gene Expression Omnibus data repository (accession number: GSE8070, GSE28735, GSE15550 and GSE19650).
statistical significant difference in AUTS2 expression levels between pancreatic tumor tissues and adjacent non-tumor controls (Fig. 1B). Should we stop at this step and think that AUTS2 is not a bad guy in pancreatic cancer progression? Absolutely not. Further analyses show that AUTS2 is overexpressed in pancreatic cancer cell lines derived from liver metastases compared with those from primary sites (Fig. 1C), which suggests that AUTS2 may be involved in liver metastasis of pancreatic cancer. Moreover, AUTS2 expression is higher in invasive cancer tissues originating from intraductal papillary-mucinous neoplasm (IPMN) than in groups of pancreatic ductal adenocarcinoma (PDA), intraductal papillary-mucinous adenoma (IPMA) and intraductal papillary-mucinous carcinoma (IPMC) (Fig. 1D). Taken together, our results show that AUTS2 is overexpressed at the early stage embryo pancreas development and metastatic pancreatic cancers. Gene Set Enrichment Analysis (GSEA) of AUTS2 expression profiles In an attempt to explore the potential biological functions of AUTS2 in cancer progression, Gene Set Enrichment Analysis (GSEA) was performed using gene expression profiles of 96 pancreatic cancer samples (TCGA, obtained in June, 2014) [16]. Analysis results (Fig. 2) suggested that AUTS2 expressions was positively correlated with Docetaxel resistance (A), TGF-beta pathway activation (B), HEDGEHOG pathway (C) and WNT signaling pathway (D) with P = 0.0018, P = 0.0092, P < 0.0001 and P < 0.0001, respectively. It is well known that TGF-beta is the key upstream regulator of epithelial–mesenchymal transition (EMT), while HEDGEHOG and
WNT pathway are critical signaling pathways in stem cells. Hence, AUTS2 may promote chemotherapeutic resistance and cancer metastasis through EMT process and accumulation of cancer stem cells. Construction of AUTS2 centered protein–drug interaction network To elucidate the underlying molecular mechanisms in AUTS2 promoted metastasis, we constructed an AUTS2 centered protein-drug interaction network using data from Comparative Toxicogenomics Database (CTD) and literature mining. As is shown in this network, AUTS2 could activate RAC1, EP300 and CSNK2A1, which in turn lead to epithelial–mesenchymal transition (EMT) and activation of stem cell signaling (WNT signaling pathway). Furthermore, we also provided five drugs (namely Vitamin E, Trichostatin A, Resveratrol, Cyclosporine and Coumestrol) that have the potential to down regulate AUTS2 expression, which means that these drugs may help in the management of pancreatic cancer patients with liver metastases (see Fig. 3).
Discussion AUTS2 is critical in neurodevelopment and is a candidate gene for numerous neurological disorders and non-neurological diseases such as acute lymphoblastic leukemia. Two recent papers show that AUTS2 is required for cortical neuronal migration and can activate transcription, which indicates that it might play some
Y. Han et al. / Medical Hypotheses 85 (2015) 203–206
205
Fig. 2. Gene Set Enrichment Analysis (GSEA) of AUTS2 using gene expression profiles of 96 pancreatic cancers. Analysis results demonstrated that AUTS2 expressions was positively correlated with Docetaxel resistance (A), TGF-beta pathway activation (B), HEDGEHOG pathway (C) and WNT signaling pathway (D) with P = 0.0018, P = 0.0092, P < 0.0001 and P < 0.0001, respectively.
Fig. 3. AUTS2 centered interaction network. This map shows that five drugs including Resveratrol have the potential to down regulate the expression of AUTS2. While AUTS2 could activate RAC1, EP300 and CSNK2A1, which in turn lead to epithelial–mesenchymal transition (EMT) and activation of stem cell signaling (WNT signaling pathway).
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Y. Han et al. / Medical Hypotheses 85 (2015) 203–206
functional roles in cancer cells. Nevertheless, the correlation between AUTS2 and solid tumors has never been reported. In this study, we show that AUTS2 is overexpressed in liver metastases of pancreatic cancer and could be a biomarker for defining cancer subtypes. Besides, its expression is positively correlated with Docetaxel resistance, TGF-beta pathway activation, HEDGEHOG and WNT signaling pathway, which indicates that AUTS2 might play important roles in EMT and cancer stem cells. Furthermore, by construction of a protein–drug interaction network, we show that AUTS2 might promote chemotherapeutic resistance and metastasis by exerting its effect on CSNK2A1, EP300 and TP53, which in turn activate EMT and WNT signaling pathway. Now we can see the potential functions of AUTS2 in cancer progression, but are there any drugs or chemicals available for down regulating its expression? Finally, five drugs were suggested. For example, Resveratrol is reported to extend lifespan and provide cardio-neuro-protective, anti-diabetic, and anti-cancer effects by initiating a stress response that induces survival genes [17]. Here, we suggest that it could be used for the effective management of pancreatic patients with AUTS2 overexpression. In summary, our data suggests that AUTS2 overexpression is a biomarker for liver metastasis of pancreatic cancer and could help directing personalized therapies. However, wet lab experiments and clinical trials are still needed to testify our hypothesis.
Conflicts of interest statement The authors have declared that no competing interests exist.
References [1] Bakkaloglu B, O’Roak BJ, Louvi A, et al. Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am J Hum Genet 2008;82:165–73.
[2] Ben-David E, Granot-Hershkovitz E, Monderer-Rothkoff G, et al. Identification of a functional rare variant in autism using genome-wide screen for monoallelic expression. Hum Mol Genet 2011;20:3632–41. [3] Beunders G, Voorhoeve E, Golzio C, et al. Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus. Am J Hum Genet 2013;92:210–20. [4] Elia J, Gai X, Xie HM, et al. Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol Psychiatry 2010;15:637–46. [5] Nagamani SC, Erez A, Ben-Zeev B, et al. Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders. Eur J Hum Genet 2013;21:343–6. [6] Denk D, Nebral K, Bradtke J, et al. PAX5–AUTS2: a recurrent fusion gene in childhood B-cell precursor acute lymphoblastic leukemia. Leuk Res 2012;36:e178–181. [7] Edenberg HJ, Foroud T. Genetics and alcoholism. Nat Rev Gastroenterol Hepatol 2013;10:487–94. [8] Schumann G, Coin LJ, Lourdusamy A, et al. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proc Natl Acad Sci USA 2011;108:7119–24. [9] Zhang B, Xu YH, Wei SG, et al. Association study identifying a new susceptibility gene (AUTS2) for schizophrenia. Int J Mol Sci 2014;15:19406–16. [10] Hori K, Nagai T, Shan W, et al. Cytoskeletal regulation by AUTS2 in neuronal migration and neuritogenesis. Cell Rep 2014. [11] Gao Z, Lee P, Stafford JM, von Schimmelmann M, Schaefer A, Reinberg D. An AUTS2-polycomb complex activates gene expression in the CNS. Nature 2014;516:349–54. [12] Chen HH, Yu HI, Cho WC, Tarn WY. DDX3 modulates cell adhesion and motility and cancer cell metastasis via Rac1-mediated signaling pathway. Oncogene 2014. [13] Chan CH, Lee SW, Li CF, et al. Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis. Nat Cell Biol 2010;12:457–67. [14] Kim KJ, Cho KD, Jang KY, et al. Platelet-activating factor enhances tumour metastasis via the reactive oxygen species-dependent protein kinase casein kinase 2-mediated nuclear factor-kappaB activation. Immunology 2014;143:21–32. [15] Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: archive for functional genomics data sets-update. Nucleic Acids Res 2013;41:D991–995. [16] Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005;102:15545–50. [17] Sajish M, Schimmel P. A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. Nature 2014.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
AUTS2 is a potential therapeutic target for pancreatic cancer patients with liver metastases q Yong Han a,b, Guo-Qing Ru a, Xiaozhou Mou b, Hui-ju Wang b, Yingyu Ma b, Xiang-Lei He a, Zhilong Yan c, Dongsheng Huang b,c,⇑ a b c
Department of Pathology, Zhejiang Provincial People’s Hospital, Hangzhou 310014, Zhejiang, PR China Clinical Research Institute, Zhejiang Provincial People’s Hospital, Hangzhou 310014, PR China Department of General Surgery, Zhejiang Provincial People’s Hospital, Hangzhou 310014, Zhejiang, PR China
a r t i c l e
i n f o
Article history: Received 30 December 2014 Accepted 26 April 2015
a b s t r a c t Liver metastasis is a common event at the advanced stage of pancreatic malignancies. Identification of effective therapeutic targets is crucial for the management of pancreatic cancer patients with liver metastases. In this study, we show that (A) AUTS2 is overexpressed in liver metastases of pancreatic cancer and could be a biomarker for defining cancer subtypes. (B) AUTS2 expression is positively correlated with Docetaxel resistance, TGF-beta pathway activation, HEDGEHOG and WNT signaling pathway. (C) By building an AUTS2 centered protein–drug interaction network, we show that AUTS2 might promote chemotherapeutic resistance and metastasis by exerting its effect on epithelial–mesenchymal transition and WNT signaling pathway. (D) Five drugs that could down regulate the expression of AUTS2 were also suggested. These drugs might help in the treatment of pancreatic cancer patients at the stage of liver metastasis. In summary, our results indicate that AUTS2 is a candidate biomarker for defining liver metastasis of pancreatic cancer and directing personalized therapies. Ó 2015 Elsevier Ltd. All rights reserved.
Introduction Liver metastasis is the most common event at the advanced stage of pancreatic cancer. However, mechanisms underlying this process has not yet been well understood. The Autism susceptibility candidate 2 (AUTS2) is crucial in neurodevelopment and is a candidate gene for numerous neurological disorders such as autism spectrum disorders [1], intellectual disability [2,3] and developmental delay [4,5]. Literatures also show that this gene is also associated with acute lymphoblastic leukemia [6], alcoholism [7,8] and schizophrenia [9]. Lately, Kei et al. shows that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development. Loss-of-function and rescue experiments demonstrate that cytoplasmic AUTS2-Rac1 pathway is required for cortical neuronal migration and neuritogenesis in the developing brain [10]. In addition, a very recent paper published in Nature suggested that as a component of PRC1-AUTS2 complex, CK2 (CSNK2A1) neutralizes PRC1 repressive activity, whereas q Source of support: This study was supported by the Key Social Development Project of Major Science and Technology (No. 2011C13036-1). ⇑ Corresponding author at: Department of General Surgery, Zhejiang Provincial People’s Hospital, Hangzhou 30014, Zhejiang Province, PR China. Tel.: +86 0571 87666666; fax: +86 0571 85335800. E-mail address: [email protected] (D. Huang).
http://dx.doi.org/10.1016/j.mehy.2015.04.029 0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.
AUTS2-mediated recruitment of P300 (EP300) leads to gene activation [11]. Since RAC1, EP300 and CSNK2A1 play important roles in the process of metastasis among various cancer types [12–14], we assume that AUTS2 might contribute to liver metastasis of pancreatic cancer. Hypothesis AUTS2 plays critical roles in pancreatic cancer progression and is a novel therapeutic target for pancreatic cancer patients with liver metastases. Evaluation of hypothesis Expression pattern of AUTS2 in different cell lines, animal models and human samples To explore the correlation between AUTS2 and pancreatic cancer progression, several datasets were obtained from Gene Expression Omnibus (GEO) [15]. Analysis results show that AUTS2 expression is continually down regulated in the mouse pancreas development on consecutive embryo days from e12.5 to e16.5 (Fig. 1A), which indicates that AUTS2 overexpression is an early event of pancreas development. However, there is no
204
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Fig. 1. (A) AUTS2 expression levels in mouse dorsal pancreata on consecutive embryo days from e12.5 to e16.5. All others were compared with group e12.5. (B) Expression of AUTS2 in 45 matching pairs of pancreatic tumors and adjacent non-tumor tissues (P = 0.44). (C) AUTS2 expression in six pancreatic cancer cell lines. BxPC3, MIApaca-2, Mpanc 96 and Panc-1 were established from primary tumors, while CFPAC1 and L3.6pl were from liver metastases. (D) Expression of AUTS2 in tissues from normal main pancreatic duct, IPMA, IPMC and invasive cancer originating in IPMN. Statistical significance was determined by paired/unpaired, two-tailed Student’s t test. All the data was displayed as means ± s.e.m. ⁄P 6 0.05, ⁄⁄P 6 0.01, ⁄⁄⁄P 6 0.001. Datasets were extracted from the Gene Expression Omnibus data repository (accession number: GSE8070, GSE28735, GSE15550 and GSE19650).
statistical significant difference in AUTS2 expression levels between pancreatic tumor tissues and adjacent non-tumor controls (Fig. 1B). Should we stop at this step and think that AUTS2 is not a bad guy in pancreatic cancer progression? Absolutely not. Further analyses show that AUTS2 is overexpressed in pancreatic cancer cell lines derived from liver metastases compared with those from primary sites (Fig. 1C), which suggests that AUTS2 may be involved in liver metastasis of pancreatic cancer. Moreover, AUTS2 expression is higher in invasive cancer tissues originating from intraductal papillary-mucinous neoplasm (IPMN) than in groups of pancreatic ductal adenocarcinoma (PDA), intraductal papillary-mucinous adenoma (IPMA) and intraductal papillary-mucinous carcinoma (IPMC) (Fig. 1D). Taken together, our results show that AUTS2 is overexpressed at the early stage embryo pancreas development and metastatic pancreatic cancers. Gene Set Enrichment Analysis (GSEA) of AUTS2 expression profiles In an attempt to explore the potential biological functions of AUTS2 in cancer progression, Gene Set Enrichment Analysis (GSEA) was performed using gene expression profiles of 96 pancreatic cancer samples (TCGA, obtained in June, 2014) [16]. Analysis results (Fig. 2) suggested that AUTS2 expressions was positively correlated with Docetaxel resistance (A), TGF-beta pathway activation (B), HEDGEHOG pathway (C) and WNT signaling pathway (D) with P = 0.0018, P = 0.0092, P < 0.0001 and P < 0.0001, respectively. It is well known that TGF-beta is the key upstream regulator of epithelial–mesenchymal transition (EMT), while HEDGEHOG and
WNT pathway are critical signaling pathways in stem cells. Hence, AUTS2 may promote chemotherapeutic resistance and cancer metastasis through EMT process and accumulation of cancer stem cells. Construction of AUTS2 centered protein–drug interaction network To elucidate the underlying molecular mechanisms in AUTS2 promoted metastasis, we constructed an AUTS2 centered protein-drug interaction network using data from Comparative Toxicogenomics Database (CTD) and literature mining. As is shown in this network, AUTS2 could activate RAC1, EP300 and CSNK2A1, which in turn lead to epithelial–mesenchymal transition (EMT) and activation of stem cell signaling (WNT signaling pathway). Furthermore, we also provided five drugs (namely Vitamin E, Trichostatin A, Resveratrol, Cyclosporine and Coumestrol) that have the potential to down regulate AUTS2 expression, which means that these drugs may help in the management of pancreatic cancer patients with liver metastases (see Fig. 3).
Discussion AUTS2 is critical in neurodevelopment and is a candidate gene for numerous neurological disorders and non-neurological diseases such as acute lymphoblastic leukemia. Two recent papers show that AUTS2 is required for cortical neuronal migration and can activate transcription, which indicates that it might play some
Y. Han et al. / Medical Hypotheses 85 (2015) 203–206
205
Fig. 2. Gene Set Enrichment Analysis (GSEA) of AUTS2 using gene expression profiles of 96 pancreatic cancers. Analysis results demonstrated that AUTS2 expressions was positively correlated with Docetaxel resistance (A), TGF-beta pathway activation (B), HEDGEHOG pathway (C) and WNT signaling pathway (D) with P = 0.0018, P = 0.0092, P < 0.0001 and P < 0.0001, respectively.
Fig. 3. AUTS2 centered interaction network. This map shows that five drugs including Resveratrol have the potential to down regulate the expression of AUTS2. While AUTS2 could activate RAC1, EP300 and CSNK2A1, which in turn lead to epithelial–mesenchymal transition (EMT) and activation of stem cell signaling (WNT signaling pathway).
206
Y. Han et al. / Medical Hypotheses 85 (2015) 203–206
functional roles in cancer cells. Nevertheless, the correlation between AUTS2 and solid tumors has never been reported. In this study, we show that AUTS2 is overexpressed in liver metastases of pancreatic cancer and could be a biomarker for defining cancer subtypes. Besides, its expression is positively correlated with Docetaxel resistance, TGF-beta pathway activation, HEDGEHOG and WNT signaling pathway, which indicates that AUTS2 might play important roles in EMT and cancer stem cells. Furthermore, by construction of a protein–drug interaction network, we show that AUTS2 might promote chemotherapeutic resistance and metastasis by exerting its effect on CSNK2A1, EP300 and TP53, which in turn activate EMT and WNT signaling pathway. Now we can see the potential functions of AUTS2 in cancer progression, but are there any drugs or chemicals available for down regulating its expression? Finally, five drugs were suggested. For example, Resveratrol is reported to extend lifespan and provide cardio-neuro-protective, anti-diabetic, and anti-cancer effects by initiating a stress response that induces survival genes [17]. Here, we suggest that it could be used for the effective management of pancreatic patients with AUTS2 overexpression. In summary, our data suggests that AUTS2 overexpression is a biomarker for liver metastasis of pancreatic cancer and could help directing personalized therapies. However, wet lab experiments and clinical trials are still needed to testify our hypothesis.
Conflicts of interest statement The authors have declared that no competing interests exist.
References [1] Bakkaloglu B, O’Roak BJ, Louvi A, et al. Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am J Hum Genet 2008;82:165–73.
[2] Ben-David E, Granot-Hershkovitz E, Monderer-Rothkoff G, et al. Identification of a functional rare variant in autism using genome-wide screen for monoallelic expression. Hum Mol Genet 2011;20:3632–41. [3] Beunders G, Voorhoeve E, Golzio C, et al. Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus. Am J Hum Genet 2013;92:210–20. [4] Elia J, Gai X, Xie HM, et al. Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol Psychiatry 2010;15:637–46. [5] Nagamani SC, Erez A, Ben-Zeev B, et al. Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders. Eur J Hum Genet 2013;21:343–6. [6] Denk D, Nebral K, Bradtke J, et al. PAX5–AUTS2: a recurrent fusion gene in childhood B-cell precursor acute lymphoblastic leukemia. Leuk Res 2012;36:e178–181. [7] Edenberg HJ, Foroud T. Genetics and alcoholism. Nat Rev Gastroenterol Hepatol 2013;10:487–94. [8] Schumann G, Coin LJ, Lourdusamy A, et al. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proc Natl Acad Sci USA 2011;108:7119–24. [9] Zhang B, Xu YH, Wei SG, et al. Association study identifying a new susceptibility gene (AUTS2) for schizophrenia. Int J Mol Sci 2014;15:19406–16. [10] Hori K, Nagai T, Shan W, et al. Cytoskeletal regulation by AUTS2 in neuronal migration and neuritogenesis. Cell Rep 2014. [11] Gao Z, Lee P, Stafford JM, von Schimmelmann M, Schaefer A, Reinberg D. An AUTS2-polycomb complex activates gene expression in the CNS. Nature 2014;516:349–54. [12] Chen HH, Yu HI, Cho WC, Tarn WY. DDX3 modulates cell adhesion and motility and cancer cell metastasis via Rac1-mediated signaling pathway. Oncogene 2014. [13] Chan CH, Lee SW, Li CF, et al. Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis. Nat Cell Biol 2010;12:457–67. [14] Kim KJ, Cho KD, Jang KY, et al. Platelet-activating factor enhances tumour metastasis via the reactive oxygen species-dependent protein kinase casein kinase 2-mediated nuclear factor-kappaB activation. Immunology 2014;143:21–32. [15] Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: archive for functional genomics data sets-update. Nucleic Acids Res 2013;41:D991–995. [16] Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005;102:15545–50. [17] Sajish M, Schimmel P. A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. Nature 2014.