p53-Independent regulation of p21Waf1/Cip1 expression and senescence by PRMT6

Abstract

p21 is a potent cyclin-dependent kinase inhibitor that plays a role in promoting G1 cell cycle arrest and cellular senescence. Consistent with this role, p21 is a downstream target of several tumour suppressors and oncogenes, and it is downregulated in the majority of tumours, including breast cancer. Here, we report that protein arginine methyltransferase 6 (PRMT6), a type I PRMT known to act as a transcriptional cofactor, directly represses the p21 promoter. PRMT6 knock-down (KD) results in a p21 derepression in breast cancer cells, which is p53-independent, and leads to cell cycle arrest, cellular senescence and reduced growth in soft agar assays and in severe combined immunodeficiency (SCID) mice for all the cancer lines examined. We finally show that bypassing the p21-mediated arrest rescues PRMT6 KD cells from senescence, and it restores their ability to grow on soft agar. We conclude that PRMT6 acts as an oncogene in breast cancer cells, promoting growth and preventing senescence, making it an attractive target for cancer therapy.

Protein Arginine Methyltransferase 6 (Prmt6) Is Essential for Early Zebrafish Development through the Direct Suppression of gadd45αa Stress Sensor Gene

“…These functions agree with the nuclear localization of Prmt6 (25). To date, many target genes of Prmt6 have been reported, including HoxA2 (17), thrombospondin-1 (26), p21 (20), p27 (27), p53 (21), Oct4 and Nanog (28), CD41 (29), and IL-6 (24).…”

“…Other reports demonstrate that PRMT6 is up-regulated in diverse cancer types, promoting growth and suppressing apoptosis, which is of potential significance for cancer therapeutics (19,20,26). These studies suggest that the balance of Prmt6 plays an important role in proliferation and apoptosis and that further study of this protein may prove of importance to developmental biology and anticancer research.…”

Molecular Pathways: Harnessing E2F1 Regulation for Prosenescence Therapy in p53-Defective Cancer Cells

“…The critical role for p21 in senescence regulation, even independently of p53, was supported by two recent articles describing p21-dependent programmed senescence during mouse development (2, 3). As a further support to the central role for p21 in senescence, recent studies have demonstrated p21-induced senescence in p53-defective cancer cell lines (17,(19)(20)(21) and tumors in vivo (22,23 Regulation and therapeutic targeting of E2F1-driven cancer cell senescence resistance. Activity and expression of transcription factor E2F1 is regulated by upstream tumor suppressors p53, p16, and RB and by positive feedback loop between E2F1 and its target gene CIP2A.…”

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

“…According to several studies, upregulation of p21 transcription can be through p53‐dependent pathways or p53‐independent pathways 49, 50, 51, 52. The promoter of p21 contains two conserved p53‐binding sites required for p53 responsiveness after DNA damage 53.…”