YAP silencing by RB1 mutation is essential for small-cell lung cancer metastasis

Zhengming Wu; Junhui Su; Fu-Long Li; Tao Chen; Jaimie Mayner; Adam Engler; Shenghong Ma; Qingquan Li; Kun-Liang Guan

doi:10.1038/s41467-023-41585-z

YAP silencing by RB1 mutation is essential for small-cell lung cancer metastasis

Nat Commun. 2023 Sep 22;14(1):5916. doi: 10.1038/s41467-023-41585-z.

Authors

Zhengming Wu¹, Junhui Su², Fu-Long Li³, Tao Chen⁴, Jaimie Mayner⁵, Adam Engler⁵, Shenghong Ma⁶, Qingquan Li⁷, Kun-Liang Guan^{8

9}

Affiliations

¹ Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA.
² Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China.
³ College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
⁴ Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.
⁵ Department of Bioengineering, University of California, San Diego, La Jolla, CA, 92093, USA.
⁶ Wellcome Sanger Institute, Cambridge, CB10 1RQ, UK.
⁷ Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China. 061101040@fudan.edu.cn.
⁸ Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA. guankunliang@westlake.edu.cn.
⁹ School of Life Sciences, Westlake University, Hangzhou, 310030, China. guankunliang@westlake.edu.cn.

Abstract

Small cell lung cancer (SCLC) is highly lethal due to its prevalent metastasis. Most SCLCs have inactivating mutations in TP53 and RB1. We find that loss of YAP expression is key for SCLC cells to acquire rapid ameboid migration and high metastatic potential. YAP functions through its target genes CCN1/CCN2 to inhibit SCLC ameboid migration. RB1 mutation contributes to YAP transcriptional silencing via E2F7, which recruits the RCOR co-repressor complex to YAP promoter. We discover that benzamide family HDAC inhibitors stimulate YAP expression by inhibiting the RCOR-HDAC complex, thereby suppressing SCLC metastasis and improving survival in a mouse model. Our study unveils the molecular and cellular basis underlying SCLC's high metastatic potential, the previously unrecognized role of YAP in suppressing ameboid migration and tumor metastasis, and the mechanism of YAP transcription regulation involving E2F7, RCOR, and Sin3 HDAC. This study reveals a therapeutic potential of benzamides for SCLC treatment.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antipsychotic Agents*
Humans
Loss of Function Mutation
Lung Neoplasms* / genetics
Mice
Mutation
Small Cell Lung Carcinoma* / genetics

Substances

Antipsychotic Agents
Yap1 protein, mouse
Rb1 protein, mouse

Grants and funding

R01 CA268179/CA/NCI NIH HHS/United States