RNF181 promotes ferroptosis by ubiquitinating HMOX1 to inhibit gastric cancer cell proliferation and chemoresistance

Abstract

Emergence of chemotherapeutic resistance remains an important challenge in cancer treatment, especially in advanced cancers. Recent studies have shown that ferroptosis is closely associated with tumor chemoresistance, and induction of ferroptosis has been shown to reverse chemoresistance. This study focused on the important function of Ring Finger Protein 181 (RNF181) in gastric cancer and the potential mechanisms involved in chemoresistance. Here, we found that RNF181 was aberrantly activated in chemoresistant cells of gastric cancer, and high expression of RNF181 was associated with poor patient prognosis. Depletion of RNF181 inhibited the proliferation and tumorigenicity of chemoresistant cells, and increased chemotherapeutic drug sensitivity. Mechanistically, our study showed that the interaction between RNF181 and HMOX1 mediated K27-linked polyubiquitination of HMOX1 and regulated its protein stability. Upregulation of HMOX1 expression after knockdown of RNF181 resulted in excessive heme degradation and intracellular iron overload to promote ferroptosis. Generally, our study reveals the important role of RNF181 in chemoresistance in gastric cancer, and targeting RNF181 may be a rational strategy to improve the efficacy of chemotherapy in gastric cancer.