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Vitamin B₅ supports MYC oncogenic metabolism and tumor progression in breast cancer.

ABSTRACT: Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy^1-3. Consequently, spatially resolved omics-level analyses are gaining traction^4-9. Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effects of the oncogene c-MYC, a pleiotropic transcription factor that accumulates with tumor progression and influences metabolism^10,11. Through correlative mass spectrometry imaging, we show that pantothenic acid (vitamin B₅) associates with MYC-high areas within both human and murine mammary tumors, where its conversion to coenzyme A fuels Krebs cycle activity. Mechanistically, we show that this is accomplished by MYC-mediated upregulation of its multivitamin transporter SLC5A6. Notably, we show that SLC5A6 over-expression alone can induce increased cell growth and a shift toward biosynthesis, whereas conversely, dietary restriction of pantothenic acid leads to a reversal of many MYC-mediated metabolic changes and results in hampered tumor growth. Our work thus establishes the availability of vitamins and cofactors as a potential bottleneck in tumor progression, which can be exploited therapeutically. Overall, we show that a spatial understanding of local metabolism facilitates the identification of clinically relevant, tractable metabolic targets.

SUBMITTER: Kreuzaler P

PROVIDER: S-EPMC10663155 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.

Kreuzaler Peter P Inglese Paolo P Ghanate Avinash A Gjelaj Ersa E Wu Vincen V Panina Yulia Y Mendez-Lucas Andres A MacLachlan Catherine C Patani Neill N Hubert Catherine B CB Huang Helen H Greenidge Gina G Rueda Oscar M OM Taylor Adam J AJ Karali Evdoxia E Kazanc Emine E Spicer Amy A Dexter Alex A Lin Wei W Thompson Daria D Silva Dos Santos Mariana M Calvani Enrica E Legrave Nathalie N Ellis James K JK Greenwood Wendy W Green Mary M Nye Emma E Still Emma E Barry Simon S Goodwin Richard J A RJA Bruna Alejandra A Caldas Carlos C MacRae James J de Carvalho Luiz Pedro Sório LPS Poulogiannis George G McMahon Greg G Takats Zoltan Z Bunch Josephine J Yuneva Mariia M

Nature metabolism 20231109 11

Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy1-3. Consequently, spatially resolved omics-level analyses are gaining traction4-9. Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effec ...[more]

PMID: 37946084

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Project description:BackgroundGlutamine metabolism is a central metabolic pathway in cancer. Recently, reductive carboxylation of glutamine for lipogenesis has been shown to constitute a key anabolic route in cancer cells. However, little is known regarding central regulators of the various glutamine metabolic pathways in cancer cells.MethodsThe impact of PGC-1α and ERRα on glutamine enzyme expression was assessed in ERBB2+ breast cancer cell lines with quantitative RT-PCR, chromatin immunoprecipitation, and immunoblotting experiments. Glutamine flux was quantified using 13C-labeled glutamine and GC/MS analyses. Functional assays for lipogenesis were performed using 14C-labeled glutamine. The expression of glutamine metabolism genes in breast cancer patients was determined by bioinformatics analyses using The Cancer Genome Atlas.ResultsWe show that the transcriptional coactivator PGC-1α, along with the transcription factor ERRα, is a positive regulator of the expression of glutamine metabolism genes in ERBB2+ breast cancer. Indeed, ERBB2+ breast cancer cells with increased expression of PGC-1α display elevated expression of glutamine metabolism genes. Furthermore, ERBB2+ breast cancer cells with reduced expression of PGC-1α or when treated with C29, a pharmacological inhibitor of ERRα, exhibit diminished expression of glutamine metabolism genes. The biological relevance of the control of glutamine metabolism genes by the PGC-1α/ERRα axis is demonstrated by consequent regulation of glutamine flux through the citric acid cycle. PGC-1α and ERRα regulate both the canonical citric acid cycle (forward) and the reductive carboxylation (reverse) fluxes; the latter can be used to support de novo lipogenesis reactions, most notably in hypoxic conditions. Importantly, murine and human ERBB2+ cells lines display a significant dependence on glutamine availability for their growth. Finally, we show that PGC-1α expression is positively correlated with that of the glutamine pathway in ERBB2+ breast cancer patients, and high expression of this pathway is associated with reduced patient survival.ConclusionsThese data reveal that the PGC-1α/ERRα axis is a central regulator of glutamine metabolism in ERBB2+ breast cancer. This novel regulatory link, as well as the marked reduction in patient survival time associated with increased glutamine pathway gene expression, suggests that targeting glutamine metabolism may have therapeutic potential in the treatment of ERBB2+ breast cancer.

Project description:BackgroundThe activities of MYC, the androgen receptor, and its associated pioneer factors demonstrate substantial reprogramming between early and advanced prostate cancer. Although previous studies have shown a shift in cellular metabolic requirements associated with prostate cancer progression, the epigenetic regulation of these processes is incompletely described. Here, we have integrated chromatin immunoprecipitation sequencing (ChIP-seq) and whole-transcriptome sequencing to identify novel regulators of metabolism in advanced prostate tumors characterized by elevated MYC activity.ResultsUsing ChIP-seq against MYC, HOXB13, and AR in LNCaP cells, we observed redistribution of co-bound sites suggestive of differential KMT2A activity as a function of MYC expression. In a cohort of 177 laser-capture microdissected foci of prostate tumors, KMT2A expression was positively correlated with MYC activity, AR activity, and HOXB13 expression, but decreased with tumor grade severity. However, KMT2A expression was negatively correlated with these factors in 25 LuCaP patient-derived xenograft models of advanced prostate cancer and 99 laser-capture microdissected foci of metastatic castration-resistant prostate cancer. Stratified by KMT2A expression, ChIP-seq against AR and HOXB13 in 15 LuCaP patient-derived xenografts showed an inverse association with sites involving genes implicated in lipid metabolism, including the arachidonic acid metabolic enzyme PLA2G4F. LuCaP patient-derived xenograft models grown as organoids recapitulated the inverse association between KMT2A expression and fluorine-18 labeled arachidonic acid uptake in vitro.ConclusionsOur study demonstrates that the epigenetic activity of transcription factor oncogenes exhibits a shift during prostate cancer progression with distinctive phenotypic effects on metabolism. These epigenetically driven changes in lipid metabolism may serve as novel targets for the development of novel imaging agents and therapeutics.

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Vitamin B₅ supports MYC oncogenic metabolism and tumor progression in breast cancer.

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Vitamin B<sub>5</sub> supports MYC oncogenic metabolism and tumor progression in breast cancer.

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Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.

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Vitamin B&lt;sub&gt;5&lt;/sub&gt; supports MYC oncogenic metabolism and tumor progression in breast cancer.

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OmicsDI is part of the ELIXIR infrastructure

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Vitamin B₅ supports MYC oncogenic metabolism and tumor progression in breast cancer.

Vitamin B<sub>5</sub> supports MYC oncogenic metabolism and tumor progression in breast cancer.