Rhomboid Domain Containing 2 (RHBDD2) is Upregulated and Responds to Cisplatin-Induced DNA Damage in Esophageal Cancer.

As a pseudoprotease, RHBDD2 regulates tumor survival and progression in several cancers, but its expression and function in most cancers remain unclear. This study aimed to investigate the role of RHBDD2 in esophageal carcinoma (ESCA) via the use of public datasets and performing cytology experiments and RNA-seq analysis in ESCA cells. RHBDD2 was obviously upregulated and contributed to worse relapse-free survival (RFS) in patients with ESCA. Furthermore, chemotherapy increased RHBDD2 expression, and several GEO datasets also demonstrated that RHBDD2 expression was upregulated in both cisplatin-treated and resistant ESCA cells. Additionally, cytology experiments revealed that cisplatin treatment markedly upregulated the expression of RHBDD2 and γH2AX, which is a DNA damage marker, whereas RHBDD2 knockdown or overexpression affected cisplatin-induced γH2AX expression and the cytotoxic effects of cisplatin. The functional enrichment of RNA-seq data from RHBDD2-knockdown EC9706 cells suggested that RHBDD2-induced DEGs were involved in the DNA damage response and repair. Pearson's correlation analysis revealed that RHBDD2 expression was positively correlated with the expression of several genes, such as DMC1, CBX5, RAD1, DDB2, and ERCC1, which are responsible for DNA damage repair. Taken together, our results first revealed that RHBDD2 is upregulated and responds to DNA damage in ESCA, which provides new evidence for the potential role of RHBDD2 in the chemotherapy sensitivity and survival of patients with ESCA.