P53-Independent Regulation of P21Waf1/Cip1 Expression and Senescence by PRMT6

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2012 Sep 19

PMID 22987071

Citations 56

Authors

Sameer Phalke

Slim Mzoughi

Marco Bezzi

Nancy Jennifer

Wei Chuen Mok

Diana H P Low

Aye Aye Thike

Vladimir A Kuznetsov

Puay Hoon Tan

P Mathijs Voorhoeve

Ernesto Guccione

Affiliations

Soon will be listed here.

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.

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