The role and target potential of the RNA-binding protein MEX3A in lung adenocarcinoma

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The human MEX3 protein family comprises four RNA-binding proteins (RBPs), termed MEX3A-D. MEX3 proteins share a conserved domain organization, including two N-terminal RNA binding HNRNPK-homology (KH) domains, expanded intrinsically disordered regions (IDRs) and a C-terminal RING domain, implicated in E3-ligase mediated protein ubiquitination. Accordingly, MEX3 proteins were reported to serve dual, probably interconnected roles in modulating RNA fate as well as protein expression, function and turnover. In preliminary analyses, we identified a strong oncofetal pattern of expression for MEX3A with severe upregulation in various solid cancers and association of elevated MEX3A abundance with reduced survival probability. This was most prominent in lung adenocarcinoma (LUAD). In LUAD-derived tumor cells, MEX3A depletion/deletion impairs proliferation, self-renewal, anoikis resistance as well as migration and substantially interferes with tumor growth in subcutaneous xenograft models. Strikingly, the in vivo depletion of MEX3A via nanoparticle-delivered siRNA pools severely reduced xenograft tumor growth. Our studies suggest that pro-oncogenic roles of MEX3A rely on the stabilization of mRNAs encoding cell cycle regulators and promoting the ubiquitination-dependent decay of the tumor suppressor TP53. Collectively, these findings indicate that MEX3A is a potent pro-oncogenic oncofetal RBP with therapeutic target potential in cancer treatment. The studies proposed within the RU5433 framework aim to delineate the molecular mechanisms and key effector pathways underlying MEX3A function in LUAD and other cancers. For in vivo evaluation, we have established conditional LSL-MEX3A (lox-stop-lox) lung cancer mouse models to explore the pro-tumorigenic roles of MEX3A in synergy with KRAS and TP53 deregulation. In view of the dual roles of MEX3A, the research plan bundles interdisciplinary expertise in RNA/RBP-centered tumor biology (Hüttelmaier) and structural/modification-focused protein mass spectrometry (Sinz). This complementary expertise will allow to decipher the molecular mechanisms underlying MEX3A function in cancer to ultimately explore its therapeutic target potential in cancer treatment.