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April 24th, 2025
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Indian Institute of Technology, Dharwad
cancer biology
biorxiv

TGFb Regulated Small GTPase RHOV interact with PEAK1 and drive MYC Expression to Promote Cellular Proliferation, Migration and Etoposide resistance

Chatterjee, A.Open in Google Scholar•Acharya, D.Open in Google Scholar•Bhandari, N.Open in Google Scholar•Bhat, P.Open in Google Scholar•Chaube, B. K.Open in Google Scholar•Shukla, S.Open in Google Scholar

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, driven by tumor heterogeneity, metastasis, and therapeutic resistance. While Rho GTPases are well-established regulators of oncogenic processes, the role of the atypical GTPases in NSCLC remains unexplored. Here, we identified RHOV as one of the commonly upregulated Rho GTPases in NSCLC. Analysis of four independent patient cohorts revealed that elevated RHOV expression serves as a robust and independent prognosticator of NSCLC patients specifically early-stage disease. Functionally, RHOV knockdown significantly inhibited cell proliferation, whereas its overexpression enhanced proliferation. Similarly, RHOV depletion suppressed cell migration by disrupting cytoskeletal dynamics, while its overexpression promoted migratory capacity. Mechanistically, we demonstrated that RHOV is a direct transcriptional target of the TGFb-SMAD3 signaling pathway. RNA-seq analysis identified MYC as a critical downstream mediator of RHOV; RHOV knockdown reduced MYC expression, impairing mitochondrial oxidative phosphorylation and inducing ROS-mediated DNA damage, a phenotype rescued by MYC overexpression. Furthermore, RHOV inhibition sensitized NSCLC cells to etoposide but not doxorubicin. immunoprecipitation coupled with LC-MS revealed PEAK1 as a key interactor of RHOV. The RHOV-PEAK1 complex proved essential for NSCLC proliferation, as PEAK1 silencing abolished RHOV-driven MYC upregulation and tumor growth. This axis sustains MYC levels and activates PI3K/MAPK signaling. Intriguingly, PEAK1 depletion elevated TGFb levels, which suppressed RHOV expression, establishing a negative feedback loop wherein PEAK1 maintains RHOV by inhibiting TGFb; signaling. Collectively, our findings establish RHOV as a prognostic biomarker and a driver of NSCLC progression via the RHOV-PEAK1-MYC axis, highlighting its potential as a therapeutic target.

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