FAK-mediated phosphorylation at Y464 regulates p85β nuclear translocation to promote tumorigenesis of ccRCC by repressing RB1 expression
Yanhua Zhang,
Baoyu He,
Dong Zhang,
Yifan Zhang,
Chengkun Chen,
Wenye Zhang,
Shiyi Yang,
Meilian Yao,
Gaoping Cui,
Jun Gu,
Ting Wang,
Zhang Lin,
Youben Fan,
Zuquan Xiong,
Yujun Hao
Affiliations
Yanhua Zhang
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
Baoyu He
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China; Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272029, China
Dong Zhang
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
Yifan Zhang
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
Chengkun Chen
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
Wenye Zhang
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China; Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China
Shiyi Yang
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
Meilian Yao
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
Gaoping Cui
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
Jun Gu
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
Ting Wang
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
Zhang Lin
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
Youben Fan
Department of Thyroid-Breast-Hernia Surgery, Thyroid and Parathyroid Center, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
Zuquan Xiong
Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China; Corresponding author
Yujun Hao
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China; Corresponding author
Summary: PI3K regulatory subunit p85s normally stabilizes and regulates catalytic subunit p110s in the cytoplasm. Recent studies show that p110-free p85s in the nucleus plays important roles in biological processes. However, the mechanisms by which p85s translocate into the nucleus remain elusive. Here, we describe the mechanism by which p85β translocates into the nucleus to promote ccRCC tumorigenesis. Phosphorylation of p85β at the Y464 by FAK facilitates its nuclear translocation in the kidney through enhancing the binding of p85β to KPNA1. PIK3R2/p85β is highly expressed in ccRCC samples and associated with overall survival of ccRCC patients. Nuclear but not cytoplasmic p85β performs oncogenic functions by repressing RB1 expression and regulating the G1/S cell cycle transition. Nuclear p85β represses RB1 expression by stabilizing histone methyltransferase EZH1/EZH2 proteins. Last, the FAK inhibitor defactinib significantly suppresses the tumor growth of ccRCC with high p85β Y464 levels.
