Faculty, Staff and Student Publications

Language

English

Publication Date

6-5-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-60329-9

PMID

40473600

PMCID

PMC12141477

PubMedCentral® Posted Date

6-5-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Lung Neoplasms, Transcription Factors, Animals, DNA Helicases, Cell Line, Tumor, Nuclear Proteins, Mice, Cell Movement, Gene Expression Regulation, Neoplastic, Carcinoma, Renal Cell, Kidney Neoplasms, Female, Gene Silencing, CRISPR-Cas Systems, Renal cell carcinoma, Metastasis, Cell invasion

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.