DNMT3B Oncogenic Activity in Human Intestinal Cancer Is Not Linked to CIMP or BRAFV600E Mutation

Abstract

Approximately 10% of human colorectal cancer (CRC) are associated with activated BRAFV600E mutation, typically in absence of APC mutation and often associated with a CpG island methylator (CIMP) phenotype. To protect from cancer, normal intestinal epithelial cells respond to oncogenic BRAFV600E by activation of intrinsic p53 and p16-dependent tumor suppressor mechanisms, such as cellular senescence. Conversely, CIMP is thought to contribute to bypass of these tumor suppressor mechanisms, e.g. via epigenetic silencing of tumor suppressor genes, such as p16. It has been repeatedly proposed that DNMT3B is responsible for BRAFV600E-induced CIMP in human CRC. Here we set out to test this by in silico, in vitro, and in vivo approaches. We conclude that although both BRAFV600E and DNMT3B harbor oncogenic potential in vitro and in vivo and show some evidence of cooperation in tumor promotion, they do not frequently cooperate to promote CIMP and human intestinal cancer.

DNMT3b affects colorectal cancer development by regulating FLI1 through DNA hypermethylation

“…MacKenzie et al revealed that DNMT3b was frequently amplified and overexpressed in CRC. 28 DNMT3b was upregulated in endometrial cancer samples from patients, and promoted endometrial cancer cell proliferation, as evidenced by assays of cell viability, cell cycle, colony formation. 29 Camero et al provided that DNMT3b depletion induced significant DNA damage and impaired the DNA repair machinery in rhabdomyosarcoma.…”

“…In this study, we found only DNMT3b showed significant overexpression in both patients with COAD and READ and CRC cells among three DNMTs. MacKenzie et al revealed that DNMT3b was frequently amplified and overexpressed in CRC 28 . DNMT3b was upregulated in endometrial cancer samples from patients, and promoted endometrial cancer cell proliferation, as evidenced by assays of cell viability, cell cycle, colony formation 29 .…”

PHF14 enhances DNA methylation of SMAD7 gene to promote TGF-β-driven lung adenocarcinoma metastasis

“…As a component in the newly identified PHF14/DNMT3B complex, DNMT3B is known as one of the two de novo DNA methyltransferases responsible for generating 5-methylcytosine by transferring the methyl-group from S-adenosyl methionine to the fifth carbon of unmethylated cytosine 47 . Previous studies have found that DNMT3B could be upregulated by TGF-β signaling activation 45 , and that DNMT3B overexpression accelerates malignant transformation, promotes cancer progression and induces drug resistance in liver cancer, colon cancer and breast cancer, through enhancing DNA hypermethylationmediated epigenetic suppression of tumor suppressor genes 18,19,[48][49][50] . Interestingly, DNMT3A, a paralogue of DNMT3B, predominantly plays a tumor-suppressive role in cancers 51 .…”