Related Experiment Video
Updated: Sep 30, 2025
Author Spotlight: Exploring Salidroside's Molecular Mechanisms in Breast Cancer Treatment
Published on: June 9, 2023
LDHA Desuccinylase Sirtuin 5 as A Novel Cancer Metastatic Stimulator in Aggressive Prostate Cancer
Oh Kwang Kwon1, In Hyuk Bang2, So Young Choi1
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.
Abstract:
Prostate cancer (PCa) is the most commonly diagnosed genital cancer in men worldwide. Around 80% of the patients who developed advanced PCa suffered from bone metastasis, with a sharp drop in the survival rate. Despite great efforts, the detailed 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 revealed 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 reduced survival rate was also confirmed. Using quantitative global succinylome analysis, we characterized a significant increase in the succinylation at lysine 118 (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 reveals the reduction of SIRT5 protein expression and LDHA-K118su as a novel mechanism involved in PCa progression, which could serve as a new target to prevent CPRC progression for PCa treatment.
Insights
Decreased Sirtuin 5 (SIRT5) protein levels correlate with aggressive prostate cancer (PCa) and reduced survival. This study identifies increased LDHA succinylation as a key driver of PCa progression and a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Prostate cancer (PCa) is a leading cause of cancer death in men, often progressing to castration-resistant PCa (CRPC) with bone metastasis.
- The molecular mechanisms driving PCa progression and CRPC remain incompletely understood.
- Sirtuin 5 (SIRT5), an NAD+-dependent desuccinylase, is implicated in cancer, but its specific role in PCa requires further investigation.
Purpose of the Study:
- To investigate the role of Sirtuin 5 (SIRT5) in prostate cancer (PCa) progression.
- To identify molecular mechanisms linking SIRT5 to PCa aggressiveness and castration-resistant PCa (CRPC).
- To explore potential therapeutic targets for PCa and CRPC based on SIRT5 function.
Main Methods:
- Quantitative analysis of SIRT5 protein levels in PCa cells across different stages.
- Global succinylome analysis to identify protein succinylation changes in PCa.
- Biochemical assays to assess lactate dehydrogenase A (LDHA) activity and PCa cell migration/invasion.
Main Results:
- Significantly decreased SIRT5 protein expression was observed in aggressive PCa cells and correlated with reduced patient survival.
- Increased succinylation at lysine 118 (K118su) of lactate dehydrogenase A (LDHA) was identified as a key post-translational modification.
- LDHA-K118su was found to enhance LDHA activity, promote PCa cell migration and invasion, and was elevated in PCa patients.
Conclusions:
- Reduced SIRT5 protein expression and increased LDHA succinylation (LDHA-K118su) represent a novel mechanism driving PCa progression.
- This pathway contributes to increased cell migration, invasion, and overall disease aggressiveness.
- Targeting SIRT5 or LDHA succinylation may offer new therapeutic strategies to prevent CRPC progression in prostate cancer.
