Abstract: Objective To analyze the expression of SIRT5 in pan-cancer and its relationship with prognosis and to explore the mechanism of SIRT5 regulating breast cancer proliferation through aldehyde dehydrogenase 5 family member A1(ALDH5A1). Methods cBioPortal,TNMplot,GEPIA and The Kaplan-Meier Plotter were used to analyze the differential expression of SIRT5 in a variety of tumors and its correlation with prognosis. The interacting proteins co-precipitated with the SIRT5 were analyzed by mass spectrometry. Pathway enrichment was performed for the interaction proteome, and for the combined analysis of the interaction proteome and the acylation proteome. Finally, the ALDH5A1 was focused. Then, the interaction between SIRT5 and ALDH5A1 was determined by an in vivo and in vitro immunoprecipitation(IP).SIRT5 was over-expressed or knocked down to detect acylation level and enzyme activity of ALDH5A1. Finally, the effects of SIRT5 and ALDH5A1 on breast cancer proliferation were determined by cell proliferation and cloning experiments. Results SIRT5 was highly expressed in a variety of tumors such as breast cancer and was positively correlated with poor prognosis (P＜0.05). There were multiple overlaps between SIRT5 interacting proteins and acylomics and the overlapped proteins were mainly enriched in metabolic pathways such as amino acid metabolism. SIRT5 directly interacted with ALDH5A1. SIRT5 could enhance the enzyme activity of ALDH5A1 by inducing the desuccinylation of ALDH5A1, thus promoting the proliferation of breast cancer cells (P＜0.05). Conclusions The function of SIRT5 in tumors may be specific to a heterogeneous environment and it can play a tumor-promoting role through ALDH5A1 in breast cancer. The results reported here may provide a theoretical basis for subsequent clinical targeted therapy.

Key words: SIRT5, ALDH5A1, breast cancer, proliferation