SWI/SNF ATPase silenced HLF potentiates lung metastasis in solid cancers

Jin Zhou, Austin Hepperla, Jeremy M. Simon, Kangsan Kim, Qing Hu, Chuanhai Zhang, Lei Dong, Lianxin Hu, Cheng Zhang, Chengheng Liao, Alice Fang, Yayoi Adachi, Haoyong Fu, Tao Wang, Qian Liang, Fangzhou Zhao, Hongyi Liu, Masashi Takeda, Jun Fang, Hua Zhong, Peter Ly, Lu Wang, Payal Kapur, Lin Xu, Liwei Jia, Srinivas Malladi, James Brugarolas, M. Celeste Simon (), Bo Li () and Qing Zhang ()
Additional contact information
Jin Zhou: University of Texas Southwestern Medical Center
Austin Hepperla: University of North Carolina School of Medicine
Jeremy M. Simon: University of North Carolina School of Medicine
Kangsan Kim: University of Texas Southwestern Medical Center
Qing Hu: University of Texas Southwestern Medical Center
Chuanhai Zhang: University of Texas Southwestern Medical Center
Lei Dong: University of Texas Southwestern Medical Center
Lianxin Hu: University of Texas Southwestern Medical Center
Cheng Zhang: University of Texas Southwestern Medical Center
Chengheng Liao: University of Texas Southwestern Medical Center
Alice Fang: University of Texas Southwestern Medical Center
Yayoi Adachi: University of Texas Southwestern Medical Center
Haoyong Fu: University of Texas Southwestern Medical Center
Tao Wang: University of Texas Southwestern Medical Center
Qian Liang: University of Texas Southwestern Medical Center
Fangzhou Zhao: University of Texas Southwestern Medical Center
Hongyi Liu: University of Texas Southwestern Medical Center
Masashi Takeda: University of Texas Southwestern Medical Center
Jun Fang: University of Texas Southwestern Medical Center
Hua Zhong: University of Texas Southwestern Medical Center
Peter Ly: University of Texas Southwestern Medical Center
Lu Wang: Northwestern University
Payal Kapur: University of Texas Southwestern Medical Center
Lin Xu: University of Texas Southwestern Medical Center
Liwei Jia: University of Texas Southwestern Medical Center
Srinivas Malladi: University of Texas Southwestern Medical Center
James Brugarolas: University of Texas Southwestern Medical Center
M. Celeste Simon: University of Pennsylvania
Bo Li: Southern Medical University
Qing Zhang: University of Texas Southwestern Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-19

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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-60329-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60329-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-60329-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().