SUMOylation involved in malignant progression of multiple tumors and SENP5 may improve the chemotherapy sensitivity of hypoxic tumors

ChunYan ZHANG¹Bing Han¹Yanxia Li¹Yuxiang Wang¹Min Liu¹Min Zhong JIANG¹Han Wen WU¹Xiaozhi Liu¹Yafei Liu²Mingyong Liu^1*

• ¹Tianjin Fifth Central Hospital, Tianjin, China
• ²Peking University First Hospital, Beijing, China

ABSTRACT Small ubiquitin-related modifier (SUMO), a ubiquitin-like modification protein, has been implicated in aggressive progression of various tumor types. However, a comprehensive understanding of its mechanisms and the identification of valuable therapeutic targets remain challenging. This study aimed to investigate the expression patterns and clinical significance of key members of the SUMO pathway across multiple cancers, with the goal of identifying promising targets for therapy. Our results demonstrated significant activation of SUMO signaling in numerous tumors, which was associated with poor prognosis. Notably, we found that oxygen levels modulate tumor sensitivity to chemotherapy by regulating SUMOylation. Pharmacological inhibition of the core SUMOylation enzyme UBC9 using the chemical inhibitor Spectinomycin B1 UBC9 effectively suppressed tumor progression through widespread deSUMOylation of substrate proteins. However, this approach also induces side effects in organoids derived from normal mouse organs. In contrast, SENP5 showed tumor-specific overexpression and was found to specifically mediated the removal of SUMO2/3 modifications from target proteins, affecting a narrower set of pathways. Based on these findings, we hypothesized that targeting SENP5 may enable more precise inhibition of SUMOylation with reduced off-tumor toxicity. We validated these hypotheses-specifically, the role of SENP5 in promoting tumor progression via selective deSUMOylation and its potential as a therapeutic target with an improved safety profile-using experimental models including tumor cell lines, tumor-derived organoids, and fetal mouse liver and kidney organoids. In summary, our results indicate that inhibition of the SUMOylation pathway is a promising therapeutic strategy. The broader implication of our study is that the precision and safety of this approach are contingent upon targeting specific components such as SENP5, which offers a superior therapeutic window by avoiding the adverse effects associated with global SUMOylation inhibition.