SWI/SNF ATPase silenced HLF potentiates lung metastasis in solid cancers
Abstract
Abstract Metastasis is the main cause of cancer-related deaths, yet the underlying mechanisms remain elusive. Here, using clear cell renal cell carcinoma (ccRCC), a tumor type with frequent lung metastases, we conduct an in vivo genome-wide CRISPR-Cas9 screen and identify HLF as a potent suppressor of lung metastasis. HLF depletion enhances ccRCC cell migration and lung metastasis, whereas HLF overexpression abrogates these effects. In ccRCC patients, HLF expression is reduced at metastatic sites and associates with epigenetic silencing mediated by the SWI/SNF ATPase subunit BRG1. HLF levels negatively correlate with migration potential in collagen. Mechanistically, HLF regulates LPXN expression, modulating the integration of collagen’s mechanical cues with the actin cytoskeleton through Paxillin, thereby suppressing cancer cell migration and lung metastasis. Overexpression of HLF or pharmacological inhibition of BRG1 reduces cell invasion across multiple cancer types. Our findings suggest that targeting the BRG1-HLF axis offers a promising therapeutic strategy for combating metastatic cancers.
Article Details
Authors (30)
Jin Zhou
Department of Oncology Sichuan Cancer Hospital Chengdu China
Austin Hepperla
Jeremy M. Simon
Kangsan Kim
Qing Hu
State Key Laboratory of Green Chemical Engineering and Industrial Catalysis, Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and Molecular Engineering
Chuanhai Zhang
Lei Dong
Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Lianxin Hu
Cheng Zhang
Chengheng Liao
Alice Fang
Yayoi Adachi
Haoyong Fu
Tao Wang
Qian Liang
Fangzhou Zhao
Department of Chemistry, McGill University, 801 Sherbrooke Street. W, Montreal, Quebec H3A0B8, Canada
Hongyi Liu
Masashi Takeda
Jun Fang
Hua Zhong
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Republic of Singapore
Peter Ly
Lu Wang
Payal Kapur
Lin Xu
Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Liwei Jia
Srinivas Malladi
James Brugarolas
M. Celeste Simon
Bo Li
Qing Zhang