A novel KDM5A/MPC-1 signaling pathway promotes pancreatic cancer progression via redirecting mitochondrial pyruvate metabolism
Abstract
Mitochondrial pyruvate carrier 1 (MPC-1) appears to be a tumor suppressor. In this study, we determined the regulation of MPC-1 expression by Lysine demethylase 5A (KDM5A) and critical impact of this novel KDM5A/MPC-1 signaling on PDA progression. TCGA database, paired PDA and adjacent normal pancreatic tissues, PDA tissue array and cell lines were used to determine the levels of MPC-1 and KDM5A expression, and their relationship with the clinicopathologic characteristics and overall survival (OS) of PDA patients. Both in vitro and in vivo models were used to determine biologic impacts of MPC-1 and KDM5A on PDA and mitochondrial pyruvate metabolism, and the mechanism underling reduced MPC-1 expression in PDA. The expression of MPC-1 was decreased in PDA cell lines and tissues, and negatively associated with tumor poorer differentiation, lymph nodes metastasis, higher TNM stages, and patients' overall survival (OS). Functional analysis revealed that restored expression of MPC-1 suppressed the growth, invasion, migration, stemness and tumorigenicity. Re-expression of MPC-1 stimulated the mitochondrial pyruvate metabolism and inhibited glycolysis, while MPC-1-specific inhibitor UK5099 attenuated these effects. Furthermore, KDM5A bound directly to MPC-1 promoter region and transcriptionally suppressed the expression of MPC-1 via demethylation H3K4. Consistently, KDM5A expression was elevated in PDA and promoted PDA cell proliferation in vitro and tumor growth in vivo via suppress…
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KDM5A suppresses transcription of mitochondrial pyruvate carrier-1 (MPC-1) by H3K4 trimethylation, thereby reducing mitochondrial metabolism.
“KDM5A was also found to suppress the transcription of mitochondrial pyruvate carrier-1 (MPC-1)—a mediator of pyruvate import into the mitochondrion—by H3K4 trimethylation, thereby reducing mitochondrial metabolism [114].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [114]
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References 40 · Cited by 55
- Authors
- Cui, J., Quan, M., Xie, D., Gao, Y., Guha, S., Fallon, M. B., Chen, J., & Xie, K.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Tongji University (CN)
- University of Arizona (US)
- Corresponding author
- Quan, Ming
- Chen, Jingde
- Xie, Keping
- ORCID
- Venue
- Oncogene
- Published
- 2019-10-22
- Volume
- 39
- Issue
- 5
- Pages
- 1140-1151
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2981554419
- Cited by
- 55
- References
- 40
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 16 · 2023: 11 · 2022: 9 · 2021: 11 · 2020: 4
- FWCI
- 2.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R01CA172233, R01CA195651, R01CA198090, R01CA220236)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- KDM5A, MPC1, pancreatic ductal adenocarcinoma, lysine demethylase, H3K4 demethylation, tumor suppressor, tumor progression, cancer stemness, tumor cell migration and invasion, glycolysis, UK5099, transcriptional regulation, prognostic factors
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Female, Glycolysis, Histones, Humans, Methylation, Mitochondria, Pancreatic Neoplasms, Transcription, Genetic, Signal Transduction, Gene Expression Regulation, Neoplastic, Disease Progression, Pyruvic Acid, Monocarboxylic Acid Transporters, Mitochondrial Membrane Transport Proteins, Cell Line, Tumor, Mice, Retinoblastoma-Binding Protein 2
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