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Scientists elucidate radiation-mediated COX2 regulation
Newsdesk Scientists elucidate radiation-mediated COX2 regulation
THE LANCET Oncology Vol 4 March 2003
indicated that CUGBP2 bound to and stabilised COX2 mRNA, but prevented its translation into protein (Mol Cell 2003; 11: 113–26). This result constitutes a paradigm shift”, says Anant. “No longer can we say ‘more RNA means more protein’.” Anant’s result also contrasts with previous work in which oncogenes and other factors have increased COX2 expression by stabilising its mRNA without inhibiting its translation. “This paper shows another mechanism for COX2 regulation”, comments DuBois, “and is the first to implicate CUGBP2. However, more
work is needed to determine the relevance of these results for neoplasia and to check whether CUGBP2 is involved in COX2 regulation outside radiation treatment”. Anant agrees on the need for more research. Indeed, he is hopeful that COX2 will not be the only protein involved in tumorigenesis and whose expression is downregulated by CUGBP2. “If CUGBP2 has specificity for AU-rich sequences rather than for a specific gene, increasing CUGBP2 expression might have a multitude of anticancer effects”, he speculates. Jane Bradbury
Hypermethylation of HIC1 causes cancer Researchers at the Sidney Kimmel Comprehensive Cancer Center (Johns Hopkins Medical Institutions, MD, USA) have provided the strongest evidence yet that methylation of the HIC1 gene is associated with cancer (Nat Genet 2003; 33: 197–202). The HIC1 product is thought to suppress genes controlling tumour progression, and its absence may promote tumorigenesis. But until now, the only evidence for this idea had been found in human cancers of the colon, breast, and lung in which the HIC1 gene is transcriptionally silenced by hypermethylation. “We tried to find out more about the function of this gene and its possible role in tumour causation and progression by engineering mice with only one copy of HIC1”, explains teamco-ordinator Stephen Baylin. “We then looked at the number of tumours that formed in [these mice] and at what had happened to the remaining HIC1 allele”. The HIC1 knockout mice survived for over 1 year, but then developed a range of tumours including carcinomas derived from squamous cells, islet cells, lung, liver, kidney, and gastrointestinal cells, along with lymphomas and sarcomas. “We saw twice as many tumours in the knockout mice as in the wild-types”, says lead-author Wen Yong Chen. “Although, for an unknown reason, 75% of the tumours
http://oncology.thelancet.com
Courtesy of M Esteller
Cyclo-oxygenase 2 (COX2) overexpression and tumorigenesis are known to be causally linked, but exactly how COX2 expression is controlled is an area of intense study. Researchers at Washington University School of Medicine (MO, USA) have now uncovered a new way in which COX2 expression can be inhibited. CUGBP2, a protein that binds to AU-rich sequences in COX2 mRNA, has been found to both stabilise the mRNA and inhibit its translation. Researcher Shrikant Anant says, “the potential of COX2 inhibitors for treating cancer may be improved by combining them with therapies designed to increase CUGBP2 expression. Plus we have invitro evidence that CUGBP2 overexpression kills cancer cells but not normal cells”. 10 years ago, Raymond DuBois (Vanderbilt University Medical School, TN, USA) first reported increased COX2 expression in colorectal cancers. “We focused on this cancer”, explains Dubois, “because several reports had indicated that there was a 50% reduction in mortality from colorectal cancer in people who regularly took nonsteroidal anti-inflammatory drugs”. Many tumours and premalignant lesions are now known to overexpress COX2 and scientists have begun to understand how protein expression increases during tumorigenesis and how this affects neoplastic behaviour (Trends Pharmacol Sci 2003; 24: 96–102). Response to radiation-induced apoptosis is one aspect of tumour behaviour that is influenced by COX2. 3 years ago, Japanese researchers reported that CUGBP2 was upregulated in a neuroblastoma cell line in which apoptosis had been induced. Anant and colleagues therefore decided to investigate whether CUGBP2 could be involved in COX2 regulation in response to radiation. Anant’s team found that irradiation of intestinal epithelial cells increased CUGBP2 and COX2 mRNA but, interestingly, not the amount of COX2 protein. Further experiments
Methylation stops suppressor-gene translation.
developed by male mice were carcinomas, whereas in females, 85% were lymphomas or sarcomas.” When the team looked at what might be causing the tumours, they found no deletions or other mutations in the HIC1-containing chromosome. However, methylation-specific PCR showed that the 1a promoter of HIC1 had been hypermethylated in the lymphomas and sarcomas, and that the 1b promoter had suffered dense hypermethylation in the carcinomas. “This acts like a stop signal to transcription”, says co-investigator Manel Esteller, “and strongly suggests that the HIC1 product is needed to prevent tumours”. Manuel Serrano, National Center for Biotechnology, Madrid, Spain, told TLO: “Compounds that inhibit methylating enzymes already exist. They [can] present some toxicity problems, but this work suggests that these molecules could make an impact on tumours that develop because of gene methylation.” Adrian Burton
133
For personal use. Only reproduce with permission from The Lancet Publishing Group.
THE LANCET Oncology Vol 4 March 2003
indicated that CUGBP2 bound to and stabilised COX2 mRNA, but prevented its translation into protein (Mol Cell 2003; 11: 113–26). This result constitutes a paradigm shift”, says Anant. “No longer can we say ‘more RNA means more protein’.” Anant’s result also contrasts with previous work in which oncogenes and other factors have increased COX2 expression by stabilising its mRNA without inhibiting its translation. “This paper shows another mechanism for COX2 regulation”, comments DuBois, “and is the first to implicate CUGBP2. However, more
work is needed to determine the relevance of these results for neoplasia and to check whether CUGBP2 is involved in COX2 regulation outside radiation treatment”. Anant agrees on the need for more research. Indeed, he is hopeful that COX2 will not be the only protein involved in tumorigenesis and whose expression is downregulated by CUGBP2. “If CUGBP2 has specificity for AU-rich sequences rather than for a specific gene, increasing CUGBP2 expression might have a multitude of anticancer effects”, he speculates. Jane Bradbury
Hypermethylation of HIC1 causes cancer Researchers at the Sidney Kimmel Comprehensive Cancer Center (Johns Hopkins Medical Institutions, MD, USA) have provided the strongest evidence yet that methylation of the HIC1 gene is associated with cancer (Nat Genet 2003; 33: 197–202). The HIC1 product is thought to suppress genes controlling tumour progression, and its absence may promote tumorigenesis. But until now, the only evidence for this idea had been found in human cancers of the colon, breast, and lung in which the HIC1 gene is transcriptionally silenced by hypermethylation. “We tried to find out more about the function of this gene and its possible role in tumour causation and progression by engineering mice with only one copy of HIC1”, explains teamco-ordinator Stephen Baylin. “We then looked at the number of tumours that formed in [these mice] and at what had happened to the remaining HIC1 allele”. The HIC1 knockout mice survived for over 1 year, but then developed a range of tumours including carcinomas derived from squamous cells, islet cells, lung, liver, kidney, and gastrointestinal cells, along with lymphomas and sarcomas. “We saw twice as many tumours in the knockout mice as in the wild-types”, says lead-author Wen Yong Chen. “Although, for an unknown reason, 75% of the tumours
http://oncology.thelancet.com
Courtesy of M Esteller
Cyclo-oxygenase 2 (COX2) overexpression and tumorigenesis are known to be causally linked, but exactly how COX2 expression is controlled is an area of intense study. Researchers at Washington University School of Medicine (MO, USA) have now uncovered a new way in which COX2 expression can be inhibited. CUGBP2, a protein that binds to AU-rich sequences in COX2 mRNA, has been found to both stabilise the mRNA and inhibit its translation. Researcher Shrikant Anant says, “the potential of COX2 inhibitors for treating cancer may be improved by combining them with therapies designed to increase CUGBP2 expression. Plus we have invitro evidence that CUGBP2 overexpression kills cancer cells but not normal cells”. 10 years ago, Raymond DuBois (Vanderbilt University Medical School, TN, USA) first reported increased COX2 expression in colorectal cancers. “We focused on this cancer”, explains Dubois, “because several reports had indicated that there was a 50% reduction in mortality from colorectal cancer in people who regularly took nonsteroidal anti-inflammatory drugs”. Many tumours and premalignant lesions are now known to overexpress COX2 and scientists have begun to understand how protein expression increases during tumorigenesis and how this affects neoplastic behaviour (Trends Pharmacol Sci 2003; 24: 96–102). Response to radiation-induced apoptosis is one aspect of tumour behaviour that is influenced by COX2. 3 years ago, Japanese researchers reported that CUGBP2 was upregulated in a neuroblastoma cell line in which apoptosis had been induced. Anant and colleagues therefore decided to investigate whether CUGBP2 could be involved in COX2 regulation in response to radiation. Anant’s team found that irradiation of intestinal epithelial cells increased CUGBP2 and COX2 mRNA but, interestingly, not the amount of COX2 protein. Further experiments
Methylation stops suppressor-gene translation.
developed by male mice were carcinomas, whereas in females, 85% were lymphomas or sarcomas.” When the team looked at what might be causing the tumours, they found no deletions or other mutations in the HIC1-containing chromosome. However, methylation-specific PCR showed that the 1a promoter of HIC1 had been hypermethylated in the lymphomas and sarcomas, and that the 1b promoter had suffered dense hypermethylation in the carcinomas. “This acts like a stop signal to transcription”, says co-investigator Manel Esteller, “and strongly suggests that the HIC1 product is needed to prevent tumours”. Manuel Serrano, National Center for Biotechnology, Madrid, Spain, told TLO: “Compounds that inhibit methylating enzymes already exist. They [can] present some toxicity problems, but this work suggests that these molecules could make an impact on tumours that develop because of gene methylation.” Adrian Burton
133
For personal use. Only reproduce with permission from The Lancet Publishing Group.