HSP90 shields ROC1/RBX1 from proteasomal degradation by CHIP E3 ubiquitin ligase to promote lung adenocarcinoma.

The Regulator of Cullins 1 (ROC1) or RING box protein-1 (RBX1) is an essential component of the largest multiunit Cullin-RING ubiquitin ligase (CRL). Previous studies demonstrated that ROC1 is frequently overexpressed in multiple malignancies, which predicts advanced cancer stages and poor prognosis. However, the molecular mechanisms driving ROC1 overexpression in cancers remain largely unknown. Herein, we reveal that HSP90 binds to ROC1 with its N-Terminus, thus promoting ROC1 stabilization. HSP90 inhibition with the N-Terminal, but not the C-Terminal inhibitors accelerate ROC1 destabilization by facilitating its ubiquitination and subsequent degradation by CHIP E3 ligase. CHIP specifically interacts with ROC1 at its CC domain, thus promoting the K48-linked-ubiquitin-mediated degradation of ROC1 at the K26 residue. Indeed, deletion of CHIP markedly blocks HSP90-inactivation-induced ROC1 reduction. Function exploration reveals that HSP90 inhibition suppresses lung adenocarcinoma (LUAD) cell growth substantially by decreasing ROC1 abundance. In clinic, HSP90β and ROC1 are overexpressed in LUAD samples, which have positive correlation and predict poor prognosis of LUAD patients. LUAD organoids analysis reveals that HSP90 blockage promotes ROC1 destabilization and inhibits the growth of organoid cells. Taken together, the present results demonstrate the regulatory mechanism of ROC1 in malignancies and suggest a novel mechanism of the oncogenic role of HSP90 to promote lung tumorigenesis.