Abstract
KLF4 is an important regulator of cell-fate decision, including DNA damage response and apoptosis. We identify a novel interplay between protein modifications in regulating KLF4 function. Here we show that arginine methylation of KLF4 by PRMT5 inhibits KLF4 ubiquitylation by VHL and thereby reduces KLF4 turnover, resulting in the elevation of KLF4 protein levels concomitant with increased transcription of KLF4-dependent p21 and reduced expression of KLF4-repressed Bax. Structure-based modelling and simulations provide insight into the molecular mechanisms of KLF4 recognition and catalysis by PRMT5. Following genotoxic stress, disruption of PRMT5-mediated KLF4 methylation leads to abrogation of KLF4 accumulation, which, in turn, attenuates cell cycle arrest. Mutating KLF4 methylation sites suppresses breast tumour initiation and progression, and immunohistochemical stain shows increased levels of both KLF4 and PRMT5 in breast cancer tissues. Taken together, our results point to a critical role for aberrant KLF4 regulation by PRMT5 in genome stability and breast carcinogenesis.
Original language | English (US) |
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Article number | 8419 |
Journal | Nature communications |
Volume | 6 |
DOIs | |
State | Published - Sep 30 2015 |
Funding
We are grateful to Drs Wade Harper and Jianping Jin for kindly providing the TAP purification vector. We appreciate Drs Jeff Brodsky and Marc W. Kirschner for reading and discussing our manuscript. We thank Tao Cheng laboratory members for help to package lentivirus to establish stable lines. We thank Dr Xinghua Lu for helping us for bioinformatic heat map analysis. We thank Dr Sterogios Moschos for the advise on the performance of IHC analysis. We also appreciate proteomic core facilities at the Rockefeller University and the University of Pittsburgh for their service on protein identification as well as methylation analyses. This work is supported by grants CA154695, R01 GM086238, U54 HG008540-01 and 5U19AI068021-6556 from the National Institute of Health as well as National Breast Cancer Foundation, Breast Cancer Research Foundation and CPRIT RP150245.
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy