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

ABSTRACT: Metastasis is the main cause of cancer-related deaths, yet the underlying mechanisms remain elusive. Using clear cell renal cell carcinoma (ccRCC), a tumor type with frequent lung metastases, we conducted an in vivo genome-wide CRISPR-Cas9 screen and identified HLF as a potent suppressor of lung metastasis. While HLF translocation is known as an oncogenic event in leukemia, its role in solid cancers remains unclear. Our study revealed that HLF depletion enhanced ccRCC migration and lung metastasis, whereas HLF overexpression abrogated these effects. This finding extended to multiple solid tumor types. In ccRCC patients, HLF expression was reduced at metastatic sites and associated with epigenetic silencing. HLF levels negatively correlated with migration potential in collagen. Mechanistically, HLF regulated leupaxin expression, affecting the integration of collagen stiffness and the actin cytoskeleton through paxillin, thereby repressing cancer cell migration and lung metastasis. These data indicate that HLF influences lung metastasis through cell-collagen interactions in solid tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272563 | GEO | 2025/04/22

REPOSITORIES: GEO

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Project description:Although the consequences of genotoxic injury include cell cycle arrest and apoptosis, cell survival responses after genotoxic injury can produce intrinsic death-resistance and contribute to the development of a transformed phenotype. Protein tyrosine phosphatases (PTPs) are integral components of key survival pathways, and are responsible for their inactivation, while PTP inhibition is are often associated with enhanced cell proliferation. Our aim was to elucidate signaling events that modulate cell survival after genotoxin exposure. Diploid human lung fibroblasts (HLF) were treated with Cr(VI) (as Na2CrO4), a well known human respiratory carcinogen that induces a wide spectrum of DNA damage, in the presence and absence of a broad-range PTP inhibitor, sodium orthovanadate. Notably, PTP inhibition abrogated Cr(VI)-induced clonogenic lethality. The enhanced survival of Cr(VI)-exposed cells after PTP inhibition was predominantly due to a bypass of cell cycle arrest and was not due to decreased Cr uptake as evidenced by unchanged Cr-DNA adduct burden. Additionally, the bypass of Cr-induced growth arrest by PTP inhibition, was accompanied by a decrease in Cr(VI)-induced expression of cell cycle inhibiting genes, and an increase in the Cr(VI)-induced expression of cell cycle promoting genes. Importantly, PTP inhibition resulted in an increase in forward mutations at the HPRT locus, supporting the hypothesis that PTP inhibition in the presence of DNA damage may lead to genomic instability, via bypass of cell cycle checkpoints. Experiment Overall Design: Experimental factor was chemical treatment type (3 of them) Experiment Overall Design: (1) No: HLF 1-1, HLF 1-2, HLF 1-3, HLF 1-4 Experiment Overall Design: (2) 1uM Cr(VI): HLF 3-1, HLF 3-2, HLF 3-3, HLF 3-4 Experiment Overall Design: (3) 10uM SOV + 1uM Cr(VI): HLF 4-1, HLF 4-2, HLF 4-3, HLF 4-4 Experiment Overall Design: Biological replicates: 4 different RNA extractions from 4 different cell cultures=quadruplicate per chemical treatment type

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

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