bims-prolim 2025-04-27 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–04–27
six papers selected by
Bruna Martins Garcia, CABIMER

Warburg effect and lactylation in cancer: mechanisms for chemoresistance.
MeCP2 Lactylation Protects against Ischemic Brain Injury by Transcriptionally Regulating Neuronal Apoptosis.
Citrullination in health and disease: From physiological function to gene regulation.
O-GlcNAcylation of FBP1 promotes pancreatic cancer progression by facilitating its Lys48-linked polyubiquitination in hypoxic environments.
SIRT3 functions as an eraser of histone H3K9 lactylation to modulate transcription for inhibiting the progression of esophageal cancer.
Identification of gene signatures associated with lactation for predicting prognosis and treatment response in breast cancer patients through machine learning.

Mol Med. 2025 Apr 22. 31(1): 146

Warburg effect and lactylation in cancer: mechanisms for chemoresistance.

Wenjie Zhang, Min Xia, Jiahui Li, Gaohua Liu, Yan Sun, Xisha Chen, Jing Zhong.

  In the clinical management of cancers, the emergence of chemoresistance represents a profound and imperative "pain point" that requires immediate attention. Understanding the mechanisms of chemoresistance is essential for developing effective therapeutic strategies. Importantly, existing studies have demonstrated that glucose metabolic reprogramming, commonly referred to as the Warburg effect or aerobic glycolysis, is a major contributor to chemoresistance. Additionally, lactate, a byproduct of aerobic glycolysis, functions as a signaling molecule that supports lysine lactylation modification of proteins, which also plays a critical role in chemoresistance. However, it is insufficient to discuss the role of glycolysis or lactylation in chemoresistance from a single perspective. The intricate relationship between aerobic glycolysis and lactylation plays a crucial role in promoting chemoresistance. Thus, a thorough elucidation of the mechanisms underlying chemoresistance mediated by aerobic glycolysis and lactylation is essential. This review provides a comprehensive overview of these mechanisms and further outlines that glycolysis and lactylation exert synergistic effects, promoting the development of chemoresistance and creating a positive feedback loop that continues to mediate this resistance. The close link between aerobic glycolysis and lactylation suggests that the application of glycolysis-related drugs or inhibitors in cancer therapy may represent a promising anticancer strategy. Furthermore, the targeted application of lactylation, either alone or in combination with other treatments, may offer new therapeutic avenues for overcoming chemoresistance.

Keywords:  Cancer; Cancer therapy; Chemoresistance; Glycolysis; Lactylation

DOI:  https://doi.org/10.1186/s10020-025-01205-6
Adv Sci (Weinh). 2025 Apr 24. e2415309

MeCP2 Lactylation Protects against Ischemic Brain Injury by Transcriptionally Regulating Neuronal Apoptosis.

Min Sun, Yuxin Zhang, Rui Mao, Yan Chen, Pinyi Liu, Lei Ye, Siyi Xu, Junqiu Jia, Shu Shu, Huiya Li, Yanping Yin, Shengnan Xia, Yanting Chen, Yun Xu.

  Lactate plays diverse roles in brain pathophysiology, including ischemic stroke. Here, the role of lysine lactylation, an epigenetic modification of lactate, in cerebral ischemia is investigated. Using a mouse model of transient middle cerebral artery occlusion, increased brain lactate levels and global protein lactylation are observed. Proteomics analysis reveals significant lactylation of non-histone proteins in the ischemic penumbra. Lactylation of MeCP2, a transcriptional regulator, is identified as a protective mechanism against stroke-induced neuronal death. Inhibition of MeCP2 lactylation through chemical or genetic manipulation increases infarct volume and aggravates neurological deficits. Mechanistically, MeCP2 lactylation at K210/K249 represses the transcription of apoptosis-associated genes, including Pdcd4 and Pla2g6, thereby attenuating neuronal apoptosis. Additionally, HDAC3 and p300 are identified as key enzymes that regulate MeCP2 lactylation post-stroke. The findings suggest that MeCP2 lactylation offers a potential therapeutic target for alleviating neuronal damage and improving stroke outcomes.

Keywords:  MeCP2 lactylation; ischemic stroke; lactylation; neuronal apoptosis; transcriptional regulation

DOI:  https://doi.org/10.1002/advs.202415309
Genes Dis. 2025 Jul;12(4): 101355

Citrullination in health and disease: From physiological function to gene regulation.

Xiaoya Zhang, Guiqiu Xie, Lang Rao, Chaoguang Tian.

  Protein citrullination involves the deimination of arginine or methylarginine residues in peptide chains to form citrulline by peptidyl arginine deiminases. This process is an important protein post-translational modification that affects molecular structure and function of various proteins, including histones. In recent years, protein citrullination has attracted widespread attention for its influence on gene transcription. Studies on the impact of protein citrullination modification on chromatin structure remodeling and the establishment of gene regulatory networks have made rapid progress. In this review, we briefly summarize the physiological functions of protein citrullination modification. Specifically, we comprehensively outline the latest progress in the study of the role of protein citrullination modification in gene transcription regulation, focusing on the interaction of protein citrullination with other post-translational modifications.

Keywords:  Citrullination; Deimination; Histone; Peptidyl arginine deiminase; Therapeutic interventions; Transcriptional control

DOI:  https://doi.org/10.1016/j.gendis.2024.101355
Oncogenesis. 2025 Apr 22. 14(1): 11

O-GlcNAcylation of FBP1 promotes pancreatic cancer progression by facilitating its Lys48-linked polyubiquitination in hypoxic environments.

Yi Zhu, Xiaoman He, Xiaojing Ma, Yan Zhang, Wei Feng.

Fructose-1,6-bisphosphatase 1 (FBP1), a rate-limiting enzyme in gluconeogenesis, is important for cancer progression. The post-translational regulation of FBP1 in hypoxic environments is still unclear. Here, we report that FBP1 is down-regulated, and a low expression level of FBP1 predicts a poor prognosis in pancreatic cancer. A hypoxic environment makes FBP1 more prone to degradation, and this effect can be reversed by inhibiting global O-GlcNAcylation signalling. O-linked N-acetylglucosamine transferase (OGT) interacts with FBP1 and induces its O-GlcNAcylation at serine 47 residue (FBP1-S47) to modulate its protein function in pancreatic cancer cells. O-GlcNAcylation of FBP1-S47 promotes FBP1 degradation and also influences the expression of canonical HIF-1α target genes involved in glucose metabolism, resulting in an increase in glucose uptake and lactate secretion in pancreatic cancer cells. In addition, O-GlcNAcylation of FBP1-S47 facilitates FBP1 K48-linked polyubiquitination at lysine 51 residue (FBP1-K51), in which GlcNAc moiety can serve as a prerequisite for an FBP1 ubiquitin ligase. FBP1 (K51) K48-linked polyubiquitination mediated protein degradation can also promote cancer progression, similarly to the O-GlcNAcylation of FBP1-S47. Our data uncover a mechanism whereby FBP1 can be regulated by a protein O-GlcNAcylation-polyubiquitination axis, paving the way to cancer cell metabolic reprogramming.

DOI: https://doi.org/10.1038/s41389-025-00555-4
Mol Cell Proteomics. 2025 Apr 17. pii: S1535-9476(25)00071-4. [Epub ahead of print] 100973

SIRT3 functions as an eraser of histone H3K9 lactylation to modulate transcription for inhibiting the progression of esophageal cancer.

Chen Chen, Yingao Zhang, Yong Zang, Zilong Fan, Yanpu Han, Xue Bai, Aiyuan Wang, Jianji Zhang, Ju Wang, Kai Zhang.

  Lysine lactylation (Kla) links lactate metabolism to epigenetic regulation, playing a key role in modulation of gene expression in tumor and immune microenvironment. Our recent study shows that HBO1-mediated histone H3K9la activates the transcription of genes encoding tumorigenesis, suggesting the potential significance of intervening in this Kla site for tumor therapy. Evidence so far indicates that traditional deacetylases can catalyse the removal of Kla, however, the precise demodifying enzyme to histone H3K9la in vivo and functional consequence remain elusive. Herein, we combined an antibody-based proximity labeling approach with mass spectrometry analysis to identify SIRT3 as a major binder to histone H3K9la and showed the specific catalysis of SIRT3 for the removal of lactylation. Molecular docking further revealed the molecular mechanism of the binding of Histone H3K9la to SIRT3. More importantly, SIRT3 can specifically modulate gene transcription by regulating H3K9la, inhibiting the progression of esophageal squamous cancer cells (ESCC). Together, our work identifies the specific delactylase of H3K9la and reveals an H3K9la-mediated molecular mechanism catalysed by SIRT3 for gene transcription regulation in ESCC, and our findings provide an opportunity to investigate the physiological significance of Kla controlled by SIRT3 in cancer.

Keywords:  Epigenetics; Esophageal squamous cell carcinoma; Gene transcription; Histone lactylation; Proteomics

DOI:  https://doi.org/10.1016/j.mcpro.2025.100973
Sci Rep. 2025 Apr 19. 15(1): 13575

Identification of gene signatures associated with lactation for predicting prognosis and treatment response in breast cancer patients through machine learning.

Jinfeng Zhao, Longpeng Li, Yaxin Wang, Jiayu Huo, Jirui Wang, Huiwen Xue, Yue Cai.

  As a newly discovered histone modification, abnormal lactation has been found to be present in and contribute to the development of various cancers. The aim of this study was to investigate the potential role between lactylation and the prognosis of breast cancer patients. Lactylation-associated subtypes were obtained by unsupervised consensus clustering analysis. Lactylation-related gene signature (LRS) was constructed by 15 machine learning algorithms, and the relationship between LRS and tumor microenvironment (TME) as well as drug sensitivity was analyzed. In addition, the expression of genes in the LRS in different cells was explored by single-cell analysis and spatial transcriptome. The expression levels of genes in LRS in clinical tissues were verified by RT-PCR. Finally, the potential small-molecule compounds were analyzed by CMap, and the molecular docking model of proteins and small-molecule compounds was constructed. LRS was composed of 6 key genes (SHCBP1, SIM2, VGF, GABRQ, SUSD3, and CLIC6). BC patients in the high LRS group had a poorer prognosis and had a TME that promoted tumor progression. Single-cell analysis and spatial transcriptome revealed differential expression of the key genes in different cells. The results of PCR showed that SHCBP1, SIM2, VGF, GABRQ, and SUSD3 were up-regulated in the cancer tissues, whereas CLIC6 was down-regulated in the cancer tissues. Arachidonyltrifluoromethane, AH-6809, W-13, and clofibrate can be used as potential target drugs for SHCBP1, VGF, GABRQ, and SUSD3, respectively. The gene signature we constructed can well predict the prognosis as well as the treatment response of BC patients. In addition, our predicted small-molecule complexes provide an important reference for personalized treatment of breast cancer patients.

Keywords:  Breast cancer; Gene signature; Lactation; Tumor microenvironment

DOI:  https://doi.org/10.1038/s41598-025-98255-x