Oh Kwang Kwon^1,#, In Hyuk Bang^2,#, So Young Choi^1,#, Ju Mi Jeon¹, Ann-Yae Na¹, Yan Gao¹, Sam Seok Cho³, Sung Hwan Ki³, Youngshik Choe⁴, Jun Nyung Lee^5,6, Yun-Sok Ha^5,6, Eun Ju Bae⁷, Tae Gyun Kwon^5,6,*, Byung-Hyun Park^2,*, Sangkyu Lee^1,*

¹BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
²Department of Biochemistry and Molecular Biology, Chonbuk National University Medical School, Jeonju, Jeonbuk 54896, Republic of Korea
³College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
⁴Korea Brain Research Institute, Daegu 41068, Republic of Korea
⁵Department of Urology, School of Medicine, Kyungpook National University, Daegu 41566, Republic of Korea
⁶Department of Urology, Kyungpook National University Hospital, Daegu 41566, Republic of Korea
⁷College of Pharmacy, Chonbuk University, Jeonju, Jeonbuk 54896, Republic of Korea

^# Equal contribution.
^* Corresponding authors.

Prostate cancer (PCa) is the most commonly diagnosed genital cancer in men worldwide. Among patients who developed advanced PCa, 80% suffered from bone metastasis, with a sharp drop in the survival rate. Despite great efforts, the detail of the mechanisms underlying castration-resistant PCa (CRPC) remain unclear. Sirtuin 5 (SIRT5), an NAD⁺-dependent desuccinylase, is hypothesized to be a key regulator of various cancers. However, compared to other SIRTs, the role of SIRT5 in cancer has not been extensively studied. Here, we showed significantly decreased SIRT5 levels in aggressive PCa cells relative to the PCa stages. The correlation between the decrease in the SIRT5 level and the patient’s survival rate was also confirmed. Using quantitative global succinylome analysis, we characterized a significant increase of lysine 118 succinylation (K118su) of lactate dehydrogenase A (LDHA), which plays a role in increasing LDH activity. As a substrate of SIRT5, LDHA-K118su significantly increased the migration and invasion of PCa cells and LDH activity in PCa patients. This study investigated the reduction of SIRT5 and LDHA-K118su as a novel mechanism involved in PCa progression, which can also be proposed as a new target that can prevent CPRC progression, which is key to PCa treatment.