BEX4 inhibits the progression of clear cell renal cell carcinoma by stabilizing SH2D4A, which is achieved by blocking SIRT2 activity.

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies. Recently, the role of brain-expressed X-linked 4 (BEX4) in cancer progression has received increasing attention. This study aimed to investigate the function of BEX4 in ccRCC and to reveal the underlying mechanisms. We first confirmed that BEX4 was significantly downregulated in ccRCC by bioinformatics analysis and that patients with low BEX4 expression tended to have prolonged overall survival time. Subsequently, we confirmed that BEX4 inhibited ccRCC cell proliferation in vitro and tumorigenesis in vivo through a series of cell function assays and the establishment of a nude mouse xenograft model, respectively. Mechanistically, we found that BEX4 positively regulates the expression of Src homology 2 domain-containing 4A (SH2D4A), an inhibitor of the NOTCH pathway, which further promoted the tumor-suppressive effects of BEX4. In addition, our study confirmed that the promoting effect of BEX4 on SH2D4A was achieved by inhibiting the deacetylase sirtuin 2 (SIRT2) activity. On this basis, we found that there was a competition between acetylation and ubiquitination modifications at the K69 site of SH2DA4 and that BEX4-induced upregulation of acetylation at the k69 site stabilizes SH2D4A protein expression by inhibiting ubiquitination at the same site. In addition, dual-luciferase assays showed that the transcriptional activity of BEX4 was positively regulated by activation transcription factor 3 (ATF3). Our study suggests that BEX4 plays a role in inhibiting tumor progression in ccRCC and maybe a new diagnostic and therapeutic target for ccRCC patients.