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Malonyl-CoA Promotes Prostate Cancer Progression and Castration Resistance by Enhancing Lipogenesis and Ran Activation

ABSTRACT: Malonyl-CoA, as a key metabolite, is not only the building block for lipogenesis, but also a critical metabolic switcher to mediates flux control over mitochondrial FAs β-oxidation in cellular. However, the levels and entire functions of malonyl-CoA in malignancy and drug resistance is still unclear, especially in those characterized by abnormal lipid metabolism, such as prostate cancer (PCa). Here, we showed the levels of malonyl CoA was increased in PCa, especially in castration-resistant prostate cancer (CRPC). Abnormal accumulation of malonyl-CoA promoted lipogenesis and reprogramed multiple metabolism (including lipid, glucose and amino acid metabolism), sustaining cellular homeostasis to contribute to PCa progression. Restoration of MLYCD expression activated PREK-mediated unfolded protein reaction (UPR) via consuming malonyl-CoA. Importantly, we also found that malonyl-CoA as a donor of malonylation, promoted lysine malonylation in PCa. We identified that malonyl-CoA promoted Ran K141 malonylation, increasing Ran activity and enhancing AR nuclear translocation and transcriptional activity, finally contributing to PCa development and resistance to antiandrogens. These findings highlighted the previously unrecognized role and function of MLYCD-mediated malonyl-CoA in PCa progression via the canonical pathway (metabolic reprogramming) and the non-canonical pathway (malonylated Ran K141), systematically revealing that might be a potentially reliable biomarker and therapy for PCa.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell Of Prostate, Prostate Cancer Cell Line

DISEASE(S): Prostate Cancer

SUBMITTER: Yiheng Dai

LAB HEAD: Lijie Zhou

PROVIDER: PXD060607 | Pride | 2025-08-21

REPOSITORIES: Pride

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			Action	DRS
	YAS202306130013_1_CON1_Slot1-07_1_11595.d.zip	Other
	YAS202306130013_1_CON2_Slot1-08_1_11596.d.zip	Other
	YAS202306130013_1_CON3_Slot1-09_1_11597.d.zip	Other
	YAS202306130013_1_HIGH1_Slot1-04_1_11592.d.zip	Other
	YAS202306130013_1_HIGH2_Slot1-05_1_11593.d.zip	Other

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Project description:Lysine malonylation is an evolutionarily conserved PTM from bacteria to mammals and involves malonyl-coenzyme (CoA) as a cofactor. Since the malonyl group has an acidic carboxylic group under physiological pH, malonylated lysine is negatively charged, which might impact on protein function and enzymatic activities. Like other short-chain acyl-CoAs, malonyl-CoA can be synthesized from its corresponding short-chain acyl salt, malonate, catalyzed by malonyl-CoA synthetase (Witkowski et al., 2011). In addition, malonyl-CoA can be produced during the carboxylation of acetyl-CoA by acetyl-CoA carboxylase (ACC), the carboxylation of acetyl-CoA by propionyl-CoA carboxylase, and the β-oxidation of old-chain-length dicarboxylic acids (Peng et al., 2011). Most studies on Kmal have been performed in mammalian systems and identified thousands of malonylated sites, revealing its role in the progress of diseases like type 2 diabetes, schizophrenia, and cardiac hypertrophy (Du et al., 2015; Smith et al., 2022; Wu et al., 2022). There has been increasing interest in dissecting the regulatory roles of Kmal in several bacterial species, such as Escherichia coli (Qian et al., 2016), Bacillus amyloliquefaciens (Fan et al., 2017), Mycobacterium tuberculosis (Bi et al., 2022), and Staphylococcus aureus (Shi et al., 2021), which demonstrates that Kmal exists in diverse prokaryotic organisms and participates in the regulation of various physiological processes. Even so, whether Kmal exists and affects protein functions in streptococci remains unknown. S. mutans is considered to be the most prevalent and cariogenic species in active carious lesions of humans, residing primarily in dental plaque, which is a biofilm that forms on the tooth surfaces. During the past decades, studies of S. mutans have focused on revealing the molecular mechanisms underlying the robust biofilm formation on tooth surfaces, the metabolism of a wide variety of carbohydrates obtained from the host diet, and the adaption of numerous environmental challenges (Lemos et al., 2019). Several studies have been performed to reveal the roles of PTMs in biofilm and cariogenic virulence. Wang et al. found that the phosphorylation of VicR could inhibit the expression of the glucosyltransferases gtfBC, thereby reducing the synthesis of extracellular polysaccharides (EPS), the major component of cariogenic biofilm (Wang et al., 2021). Acetylome study on the S. mutans depicted that acetylated substrates were globally altered in the biofilm state compared to the planktonic state, and the acetylated GtfBC showed decreased activities (Lei et al., 2021; Ma et al., 2021). Our previous study revealed that the S-glutathionylation of a thioredoxin-like protein is important for interspecies competition and cariogenicity of S. mutans(Li et al., 2020). These results suggest that various PTM types exist in S. mutans and participate in diverse physiological processes. The genome of S. mutans UA159 codes an acetyl coenzyme A carboxylase (ACC), which could synthesize malonyl-CoA through the carboxylation of acetyl-CoA (Ajdić et al., 2002), implying the existence of malonylation in this bacterium. Therefore, this study aimed to confirm the existence of Kmal in S. mutans and identify the malonylated sites globally. The present findings provide a systematic view of the functional roles of Kmal in various metabolic pathways of S. mutans.

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Malonyl-CoA Promotes Prostate Cancer Progression and Castration Resistance by Enhancing Lipogenesis and Ran Activation

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