HAUS5 defines a mitogen-activated protein kinase/extracellular signal-regulated kinase-dependent epithelial–mesenchymal plasticity program and therapeutic vulnerability to Belinostat in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is characterized by high aggressiveness and limited therapeutic options. However, the molecular determinants driving ccRCC progression and therapeutic vulnerability remain incompletely defined. Through integrated bulk and single-cell transcriptomic analyses, we identified HAUS5 as a tumor-enriched factor that was highly expressed in ccRCC tissues and tumor-derived epithelial cells. Elevated HAUS5 expression was associated with adverse clinicopathological features and poor overall survival. Functional assays showed that HAUS5 depletion suppressed ccRCC cell proliferation, migration, invasion, and xenograft tumor growth. Mechanistically, HAUS5 was associated with MAPK/ERK signaling activation and epithelial–mesenchymal transition, whereas EGF partially rescued the inhibitory effects induced by HAUS5 knockdown. In addition, drug sensitivity analysis identified Belinostat as a candidate compound associated with HAUS5 expression, and functional experiments showed that Belinostat attenuated HAUS5-associated malignant phenotypes. Collectively, these findings suggest that HAUS5 contributes to ccRCC progression through a MAPK/ERK-associated EMT program and may be linked to differential sensitivity to Belinostat.