Interplay between arginine methylation and ubiquitylation regulates KLF4-mediated genome stability and carcinogenesis

Dong Hu, Mert Gur, Zhuan Zhou, Armin Gamper, Mien-Chie Hung, Naoya Fujita, Li Lan, Ivet Bahar and Yong Wan ()
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Dong Hu: University of Pittsburgh School of Medicine
Mert Gur: University of Pittsburgh School of Medicine
Zhuan Zhou: University of Pittsburgh School of Medicine
Armin Gamper: University of Pittsburgh School of Medicine
Mien-Chie Hung: The University of Texas MD Anderson Cancer Center
Naoya Fujita: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
Li Lan: University of Pittsburgh School of Medicine
Ivet Bahar: University of Pittsburgh School of Medicine
Yong Wan: University of Pittsburgh School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9419

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