Bromodomain-containing protein 9 is a prognostic biomarker associated with immune infiltrates and promotes tumor malignancy through activating notch signaling pathway in negative HIF-2α clear cell renal cell carcinoma

Abstract

HIF-2α selective inhibitor showed successful efficacy in sensitive clear cell renal cell carcinoma (ccRCC) presenting higher levels of HIF-2α compared to resistant tumors with low level of HIF-2α (negative HIF-2α ccRCC). Currently, negative HIF-2α ccRCC lacks truly effective therapeutic agents to improve the outcomes. Bromodomain-containing protein 9 (BRD9) plays a critical role in human hepatocellular carcinoma, squamous cell lung cancer, acute myeloid leukemia, and so on. However, expression and biological role of BRD9 in negative HIF-2α ccRCC is poorly understood. Clinically, we demonstrated that expression of BRD9 in negative HIF-2α ccRCC tissues was higher than that in positive HIF-2α ccRCC. Moreover, high BRD9 expression was correlated with unfavorable clinicopathological features and predicted the poor overall survival of negative HIF-2α ccRCC patients. Functionally, BRD9 knockout resulted in reduced proliferation, migration and invasion of negative HIF-2α ccRCC cells (Caki-2). In addition, BRD9 was related to the TIIC infiltration level in negative HIF-2α ccRCC tissues. Mechanistically, Gene set enrichment analysis (GSEA) showed that BRD9 was closely related to Notch signaling pathway. BRD9 knockout resulted in reduced mRNA level of Hes1 and Notch1 in negative HIF-2α ccRCC in vitro. The overexpression of NICD (Notch intracellular domain) enhanced malignant behaviors of Caki-2 cells with BRD9 knockout. And Notch inhibition led to attenuation of cell growth and reduced migration and invasion in Caki-2 cells. Overall, our results identified that BRD9 promotes the proliferation, migration and invasion of negative HIF-2α ccRCC cells by targeting Notch signaling pathway and serve as a promising biomarker for negative HIF-2α ccRCC.