BMP6 ubiquitination mediated by SMURF1 suppresses ferroptosis and diminishes sensitivity to doxorubicin in gastric cancer.

Dysregulation of bone morphogenetic protein 6 (BMP6) is found to be associated with gastric cancer development. Here, we further explored the functions of BMP6 in gastric cancer cell malignant behaviors, ferroptosis, and doxorubicin sensitivity and the mechanism driving BMP6 dysregulation. BMP6 mRNA detection was performed by quantitative polymerase chain reaction, and protein expression was tested by immunoblotting and immunohistochemistry. Subcutaneous xenograft studies were used to analyze in vivo effects. Cell growth was evaluated by CCK-8 and EdU assays. Cell invasiveness and motility were tested by transwell assay. Cell apoptosis was detected by flow cytometry. Cell ferroptosis was assessed by detecting related markers. Cytotoxicity assay was used to evaluate doxorubicin sensitivity. The relationship of the E3 ubiquitin ligase SMURF1 with BMP6 protein was predicted by UbiBrowser algorithm and verified by co-immunoprecipitation experiment and stability analysis. BMP6 expression was downregulated in gastric cancer, and its overexpression acted for in vitro suppression of gastric cancer cell growth, invasiveness, and migration. Increased BMP6 expression sensitized gastric cancer cells to doxorubicin therapy and enhanced cell ferroptosis. Mechanistically, SMURF1 mediated the ubiquitination and degradation of BMP6. Moreover, BMP6 reduction reversed sh-SMURF1-driven in vitro alterations of cell phenotypes and ferroptosis and in vivo enhancement of doxorubicin efficacy. Our study indicates that SMURF1-mediated BMP6 ubiquitination underlies the underexpression of BMP6 in gastric cancer. BMP6 upregulation induces gastric cancer cell ferroptosis and sensitizes cells to doxorubicin therapy. Our findings provide a therapeutic strategy in gastric cancer.