Role of Histone Methylation in the Regulation of Tumour Suppressor Networks

• Main Author: Neault, Mathieu
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2016
• Subjects: Biology; Cell cycle; CRISPR; Deoxyribonucleic acid; DNA; DNA methylation; Engineering; Epigenetics; Genomes; Medical research; Medicine; Melanoma; MicroRNAs; Oncology; Pancreatic cancer; Stem cells; Stomach cancer
• ISBN: 9798597020181

Cellular senescence is a tumour suppressor mechanism which prevents the proliferation of malignant cells. In normal cells, oncogenic stimuli induce a senescence response and growth arrest coordinated by tumour suppressor genes, but the loss of expression of these genes impairs the establishment of senescence in cancer cells. We studied the role of histone methylation and oncogenic histone modifiers to assess their responsibility throughout the bypass of tumour suppressor pathways.We first used a PRMT6 knock-out mouse model to recognize the potential effect of PRMT6- mediated histone arginine methylation in cancer. Herein, we report that PRMT6 catalyzes the asymmetric di-methylation of histone H3 at arginine R2 (H3R2me2a) inside the promoter region of the Trp53 gene, resulting in the transcriptional repression of p53. In mice, functional inactivation of p53 is sufficient to bypass oncogene-induced senescence (OIS). We demonstrated that the overexpression of PRMT6 cooperates with oncogenic Ras in the bypass of OIS, suggesting an important role for histone arginine methylation mediated by PRMT6 in promoting tumourigenesis.In the second part of my thesis, I describe miR-137 as an inhibitor of KDM4A expression. KDM4A is a histone lysine demethylase participating in gene repression and the bypass of OIS to promote tumourigenesis in vivo. Specifically, KDM4A targets CHD5, a tumour suppressor and positive regulator p53 expression. We observed that miR-137 expression is lost in Ras-dependent pancreatic cancer. Moreover, restoration of its expression led to cellular growth arrest and senescence in pancreatic cancer cells. We used short hairpin inhibitors of p53 and p16INK4A to dissect the senescence pathways controlled by miR-137 and noticed that both ARF/p53 and p16INK4A/pRb tumour suppressor pathways were independently induced by miR-137. Importantly, expression of miR-137 is enhanced upon Ras activation, and the inhibition of miR-137 activity led to the bypass of OIS. These results suggest that miR-137 targets KDM4A to mediate senescence in response to oncogenic Ras, and that silencing of miR-137 could promote the Ras-driven transformation of pancreatic cancer cells.The work presented in this thesis emphasizes on the importance of the senescence response in tumour suppression. Our results provide a connection between deregulated histone methylation and defective OIS signaling in cancer. I propose that modulating the enzymes responsible for the repression of tumour suppressor genes could be a promising avenue in the prevention or treatment of cancer.