Recently, the team led by Professor Sun Xuejun from Department of General Surgery of the First Affiliated Hospital (FAH) of Xi’an Jiaotong University (XJTU) published an online Article entitled "USP51 facilitates colorectal cancer stemness and chemoresistance by forming a positive feed-forward loop with HIF1A" in an authoritative journal in the field of cell death, Cell Death & Differentiation (2022 IF: 12.4). This study clarified the role and mechanism of USP51 in drug resistance of colorectal cancer cells, provided new ideas for preventing and reversing drug resistance of colorectal cancer, identified potential novel targets for disease treatment, and added theoretical basis for formulating better clinical treatment strategies.

Chemotherapy is still one of critical approaches for the treatment of colorectal cancer, especially for metastatic colorectal cancer. Nevertheless, almost all patients who receive chemotherapy will eventually develop chemoresistance. Chemoresistance significantly limits the effectiveness of chemotherapy drugs. Studying the mechanism of chemoresistance of colorectal cancer is helpful to formulate more effective strategies to prevent or reverse drug resistance and improve the effectiveness of chemotherapy drugs, thereby increasing the survival rate of patients. Recent studies have shown that USP51 is involved in regulating DNA damage repair and tumor invasion. However, little has been known about how USP51 participates in drug resistance of colorectal cancer.

This study reveals an important molecular mechanism of chemoresistance in colorectal cancer, namely, a positive feed-forward loop is formed between USP51 and HIF1A. Under hypoxia, HIF1A binds to the promoter region of USP51, which activates the transcription of USP51, resulting in the increase of USP51 protein level. USP51 protein forms a complex with VHL E3 ligase through direct interaction with ELOC. USP51 depubiquitinates and stabilizes HIF1A protein, preventing HIF1A from being degraded through ubiquitin-proteasome pathway. HIF1A protein accumulates in cells and activates the transcription of downstream genes including USP51. The positive feed-forward loop of HIF1A-USP51 leads to the increase of USP51 and HIF1A proteins in cells. Intracellular HIF1A accumulation promotes cell survival, stemness and drug resistance. In this positive feed-forward loop, hematoxylin modification of ELOC also played a regulatory role. SUMO1 modification of ELOC K32 site inhibites the binding of ELOC to USP51 and the ubiquitination of HIF1A by USP51. SENP1-mediated delignification of ELOC promotes the combination of ELOC and USP51, accelerates the ubiquitination of HIF1A by USP51, and up-regulates the level of HIF1A protein in cells.

Studying chemoresistance in cancer treatment contributes to developing more effective treatment strategies and improving the survival rate of patients. Meantime, in-depth understanding of the effect of hypoxia on tumor cells can reveal new therapeutic targets and strategies. In fact, the findings in this study reveal the potential role of USP51 in tumor stemness and drug resistance, provide a potential therapeutic target for developing specific inhibitors, and open up a new direction for subsequent treatment methods. This study is of clinical significance for improving therapeutic effect of patients with colorectal cancer.

Doctoral student Mou Mingchao from Department of General Surgery of the FAH of XJTU is the first author, Professor Sun Xuejun and Associate Researcher Yu Junhui are co-corresponding authors, and the FAH of XJTU is the first affiliation of this article.