Abstract
We utilized whole-genome mapping of promoters that are activated by DNA hypomethylation in hepatocellular carcinoma (HCC) clinical samples to shortlist novel targets for anticancer therapeutics. We provide a proof of principle of this approach by testing six genes short-listed in our screen for their essential role in cancer growth and invasiveness. We used siRNA- or shRNA-mediated depletion to determine whether inhibition of these genes would reduce human tumor xenograft growth in mice as well as cell viability, anchorage-independent growth, invasive capacities, and state of activity of nodal signaling pathways in liver, breast, and bladder cancer cell lines. Depletion of EXOSC4, RNMT, SENP6, WBSCR22, RASAL2, and NENF effectively and specifically inhibits cancer cell growth and cell invasive capacities in different types of cancer, but, remarkably, there is no effect on normal cell growth, suggesting a ubiquitous causal role for these genes in driving cancer growth and metastasis. Depletion of RASAL2 and NENF in vitro reduces their growth as explants in vivo in mice. RASAL2 and NENF depletion interferes with AKT, WNT, and MAPK signaling pathways as well as regulation of epigenetic proteins that were previously demonstrated to drive cancer growth and metastasis. Our results prove that genes that are hypomethylated and induced in tumors are candidate targets for anticancer therapeutics in multiple cancer cell types. Because these genes are particularly activated in cancer, they constitute a group of targets for specific pharmacologic inhibitors of cancer and cancer metastasis. Clin Cancer Res; 20(12); 3118-32. ©2014 AACR.
Highlights
As extensive research revealed methylation-mediated silencing of tumor suppressor genes to be common in cancer, therapeutic strategies have been developed with the goal of decreasing DNA methylation using inhibitors of DNA methyltransferases (DNMT), enzymes catalyzing DNA methylation reaction [1, 4,5,6,7]
We reasoned that genes that are potentially critical for cancer growth and metastasis but not for normal tissue survival and physiology would be epigenetically reprogrammed and activated in tumors in comparison with normal noncancerous tissue
Our previous study of the landscape of DNA methylation in tumors from patients with liver cancer revealed a group of 230 genes that were induced and whose promoters were hypomethylated in hepatocellular carcinoma (HCC) in comparison with the matched adjacent tissue [2]
Summary
Cancer initiation and progression are driven by concurrent changes in expression of multiple genes via genetic and Authors' Affiliations: Departments of 1Pharmacology and Therapeutics and 2Medicine, McGill University Health Centre, Montreal; 3McGill Centre for Bioinformatics; and 4Sackler program for Psychobiology and Epigenetics at McGill University, Montreal, Quebec, Canada; 5Department of Nutrition Science, Purdue University, West Lafayette, Indiana; 6Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China; 7Department of Hepatology, Bangabandhu Sheikh Mujib Medical University; 8International Centre for Diarrhoeal Diseases Research, Bangladesh (icddr,b), Dhaka, Dhaka District, Bangladesh; 9Department of Medical Sciences, Toshiba General Hospital, Tokyo, Kanto, Japan; and 10Department of Pathology, Fatima Memorial Hospital College of Medicine and Dentistry Lahore, PakistanNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).B. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Epigenetic alterations leading to activation of oncogenes and prometastatic genes, silencing of tumor suppressor genes and to genome rearrangements and instability [1,2,3]. As extensive research revealed methylation-mediated silencing of tumor suppressor genes to be common in cancer, therapeutic strategies have been developed with the goal of decreasing DNA methylation using inhibitors of DNA methyltransferases (DNMT), enzymes catalyzing DNA methylation reaction [1, 4,5,6,7]
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