Hu Dong, Gur Mert, Zhou Zhuan, Gamper Armin, Hung Mien-Chie, Fujita Naoya, Lan Li, Bahar Ivet, Wan Yong
Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
Nat Commun. 2015 Sep 30;6:8419. doi: 10.1038/ncomms9419.
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.
KLF4是细胞命运决定的重要调节因子，包括DNA损伤反应和细胞凋亡。我们发现了蛋白质修饰在调节KLF4功能方面的一种新的相互作用。在这里，我们表明PRMT5对KLF4的精氨酸甲基化抑制了VHL介导的KLF4泛素化，从而减少了KLF4的周转，导致KLF4蛋白水平升高，同时KLF4依赖的p21转录增加，KLF4抑制的Bax表达降低。基于结构的建模和模拟为PRMT5识别和催化KLF4的分子机制提供了见解。在基因毒性应激后，PRMT5介导的KLF4甲基化的破坏导致KLF4积累的消除，进而减弱细胞周期停滞。突变KLF4甲基化位点可抑制乳腺肿瘤的起始和进展，免疫组织化学染色显示乳腺癌组织中KLF4和PRMT5的水平均升高。综上所述，我们的结果表明PRMT5对KLF4的异常调节在基因组稳定性和乳腺癌发生中起关键作用。
