SET1A-Mediated Mono-Methylation at K342 Regulates YAP Activation by Blocking Its Nuclear Export and Promotes Tumorigenesis

Lan Fang; Hongqi Teng; Yilin Wang; Guanghong Liao; Linjun Weng; Yaxu Li; Xinbo Wang; Jiali Jin; Chenchen Jiao; Lei Chen; Xiaoping Peng; Jiayu Chen; Yongzhi Yang; Houqin Fang; Dongyan Han; Cheng Li; Xueling Jin; Shihao Zhang; Zhongchen Liu; Min Liu; Qing Wei; Lujian Liao; Xin Ge; Bin Zhao; Dawang Zhou; Huan-Long Qin; Jun Zhou; Ping Wang

doi:10.1016/j.ccell.2018.06.002

SET1A-Mediated Mono-Methylation at K342 Regulates YAP Activation by Blocking Its Nuclear Export and Promotes Tumorigenesis

Cancer Cell. 2018 Jul 9;34(1):103-118.e9. doi: 10.1016/j.ccell.2018.06.002. Epub 2018 Jun 28.

Authors

Lan Fang¹, Hongqi Teng¹, Yilin Wang², Guanghong Liao³, Linjun Weng¹, Yaxu Li¹, Xinbo Wang¹, Jiali Jin¹, Chenchen Jiao¹, Lei Chen¹, Xiaoping Peng¹, Jiayu Chen⁴, Yongzhi Yang¹, Houqin Fang³, Dongyan Han¹, Cheng Li¹, Xueling Jin⁵, Shihao Zhang⁶, Zhongchen Liu¹, Min Liu⁷, Qing Wei¹, Lujian Liao³, Xin Ge¹, Bin Zhao⁸, Dawang Zhou⁶, Huan-Long Qin¹, Jun Zhou⁷, Ping Wang⁹

Affiliations

¹ Shanghai Tenth People's Hospital of Tongji University, School of Medicine and School of Life Science and Technology, Tongji University, Shanghai 200072, China.
² Department of Hepatic Surgery, Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
³ Shanghai Key Laboratory of Regulatory Biology, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
⁴ School of Life Science and Technology, Tongji University, Shanghai 200072, China.
⁵ Obstetrics and Gynecology Hospital of Fudan University, Fudan University, Shanghai 200032, China.
⁶ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
⁷ Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Shandong Collaborative Innovation Center of Cell Biology, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, China.
⁸ Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Zhejiang 310058, China.
⁹ Shanghai Tenth People's Hospital of Tongji University, School of Medicine and School of Life Science and Technology, Tongji University, Shanghai 200072, China. Electronic address: wangp@tongji.edu.cn.

PMID: 30008322
DOI: 10.1016/j.ccell.2018.06.002

Abstract

YAP, a key effector of Hippo pathway, is activated by its translocation from cytoplasm to nucleus to regulate gene expression and promote tumorigenesis. Although the mechanism by which YAP is suppressed in cytoplasm has been well-studied, how the activated YAP is sequestered in the nucleus remains unknown. Here, we demonstrate that YAP is a nucleocytoplasmic shuttling protein and its nuclear export is controlled by SET1A-mediated mono-methylation of YAP at K342, which disrupts the binding of YAP to CRM1. YAP mimetic methylation knockin mice are more susceptible to colorectal tumorigenesis. Clinically, YAP K342 methylation is reversely correlated with cancer survival. Collectively, our study identifies SET1A-mediated mono-methylation at K342 as an essential regulatory mechanism for regulating YAP activity and tumorigenesis.

Keywords: SET1A; YAP methylation; nuclear export; tumorigenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Active Transport, Cell Nucleus
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Cell Cycle Proteins
Cell Nucleus / enzymology*
Cell Nucleus / genetics
Cell Nucleus / pathology
Cell Proliferation
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism*
Cell Transformation, Neoplastic / pathology
Colorectal Neoplasms / enzymology*
Colorectal Neoplasms / genetics
Colorectal Neoplasms / pathology
HEK293 Cells
HeLa Cells
Histone-Lysine N-Methyltransferase / genetics
Histone-Lysine N-Methyltransferase / metabolism*
Humans
Lung Neoplasms / enzymology*
Lung Neoplasms / genetics
Lung Neoplasms / pathology
Lysine
Methylation
Mice, Inbred C57BL
Mice, Knockout
Phosphoproteins / genetics
Phosphoproteins / metabolism*
Prognosis
Protein Binding
Protein Interaction Domains and Motifs
Protein Processing, Post-Translational*
Signal Transduction
Transcription Factors
Tumor Burden
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
Phosphoproteins
Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human
Yap1 protein, mouse
Histone-Lysine N-Methyltransferase
Nsccn1 protein, mouse
Setd1A protein, human
Lysine