The PLOD2/succinate axis regulates the epithelial–mesenchymal plasticity and cancer cell stemness

Yuxin Tong; Yifei Qi; Gaofeng Xiong; Junyan Li; Timothy L. Scott; Jie Chen; Daheng He; Linzhang Li; Chi Wang; Andrew N. Lane; Ren Xu

doi:10.1073/pnas.2214942120

The PLOD2/succinate axis regulates the epithelial–mesenchymal plasticity and cancer cell stemness

Yuxin Tong, Yifei Qi, Gaofeng Xiong, Junyan Li, Timothy L. Scott, Jie Chen, Daheng He, Linzhang Li, Chi Wang, Andrew N. Lane, Ren Xu

Research output: Contribution to journal › Article › peer-review

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Abstract

Aberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in cancer progression is not completely understood. Using stable isotope-resolved metabolomics analysis, we showed that the epithelial mesenchymal transition (EMT) was associated with profound changes in metabolites, including elevation of cytoplasmic succinate levels. The treatment with cell-permeable succinate induced mesenchymal phenotypes in mammary epithelial cells and enhanced cancer cell stemness. Chromatin immunoprecipitation and sequence analysis showed that elevated cytoplasmic succinate levels were sufficient to reduce global 5-hydroxymethylcytosinene (5hmC) accumulation and induce transcriptional repression of EMT-related genes. We showed that expression of procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) was associated with elevation of cytoplasmic succinate during the EMT process. Silencing of PLOD2 expression in breast cancer cells reduced succinate levels and inhibited cancer cell mesenchymal phenotypes and stemness, which was accompanied by elevated 5hmC levels in chromatin. Importantly, exogenous succinate rescued cancer cell stemness and 5hmC levels in PLOD2-silenced cells, suggesting that PLOD2 promotes cancer progression at least partially through succinate. These results reveal the previously unidentified function of succinate in enhancing cancer cell plasticity and stemness.

Original language	English
Article number	e2214942120
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	120
Issue number	20
DOIs	https://doi.org/10.1073/pnas.2214942120
State	Published - May 16 2023

Bibliographical note

Publisher Copyright:
Copyright © 2023 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

Funding

performed FACS analysis; the Research Communications Office assisted with manuscript preparation, all of which are supported by NCI grant P30 CA177558. This study was supported by funding from the National Cancer Insititute (1R01CA207772 and R01CA215095 to R.X.).

Funders	Funder number
National Childhood Cancer Registry – National Cancer Institute	P30 CA177558, R01CA215095, 1R01CA207772

ASJC Scopus subject areas

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "The PLOD2/succinate axis regulates the epithelial–mesenchymal plasticity and cancer cell stemness",

abstract = "Aberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in cancer progression is not completely understood. Using stable isotope-resolved metabolomics analysis, we showed that the epithelial mesenchymal transition (EMT) was associated with profound changes in metabolites, including elevation of cytoplasmic succinate levels. The treatment with cell-permeable succinate induced mesenchymal phenotypes in mammary epithelial cells and enhanced cancer cell stemness. Chromatin immunoprecipitation and sequence analysis showed that elevated cytoplasmic succinate levels were sufficient to reduce global 5-hydroxymethylcytosinene (5hmC) accumulation and induce transcriptional repression of EMT-related genes. We showed that expression of procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) was associated with elevation of cytoplasmic succinate during the EMT process. Silencing of PLOD2 expression in breast cancer cells reduced succinate levels and inhibited cancer cell mesenchymal phenotypes and stemness, which was accompanied by elevated 5hmC levels in chromatin. Importantly, exogenous succinate rescued cancer cell stemness and 5hmC levels in PLOD2-silenced cells, suggesting that PLOD2 promotes cancer progression at least partially through succinate. These results reveal the previously unidentified function of succinate in enhancing cancer cell plasticity and stemness.",

author = "Yuxin Tong and Yifei Qi and Gaofeng Xiong and Junyan Li and Scott, {Timothy L.} and Jie Chen and Daheng He and Linzhang Li and Chi Wang and Lane, {Andrew N.} and Ren Xu",

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AU - Li, Junyan

AU - Scott, Timothy L.

AU - Chen, Jie

AU - He, Daheng

AU - Li, Linzhang

AU - Wang, Chi

AU - Lane, Andrew N.

AU - Xu, Ren

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N2 - Aberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in cancer progression is not completely understood. Using stable isotope-resolved metabolomics analysis, we showed that the epithelial mesenchymal transition (EMT) was associated with profound changes in metabolites, including elevation of cytoplasmic succinate levels. The treatment with cell-permeable succinate induced mesenchymal phenotypes in mammary epithelial cells and enhanced cancer cell stemness. Chromatin immunoprecipitation and sequence analysis showed that elevated cytoplasmic succinate levels were sufficient to reduce global 5-hydroxymethylcytosinene (5hmC) accumulation and induce transcriptional repression of EMT-related genes. We showed that expression of procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) was associated with elevation of cytoplasmic succinate during the EMT process. Silencing of PLOD2 expression in breast cancer cells reduced succinate levels and inhibited cancer cell mesenchymal phenotypes and stemness, which was accompanied by elevated 5hmC levels in chromatin. Importantly, exogenous succinate rescued cancer cell stemness and 5hmC levels in PLOD2-silenced cells, suggesting that PLOD2 promotes cancer progression at least partially through succinate. These results reveal the previously unidentified function of succinate in enhancing cancer cell plasticity and stemness.

AB - Aberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in cancer progression is not completely understood. Using stable isotope-resolved metabolomics analysis, we showed that the epithelial mesenchymal transition (EMT) was associated with profound changes in metabolites, including elevation of cytoplasmic succinate levels. The treatment with cell-permeable succinate induced mesenchymal phenotypes in mammary epithelial cells and enhanced cancer cell stemness. Chromatin immunoprecipitation and sequence analysis showed that elevated cytoplasmic succinate levels were sufficient to reduce global 5-hydroxymethylcytosinene (5hmC) accumulation and induce transcriptional repression of EMT-related genes. We showed that expression of procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) was associated with elevation of cytoplasmic succinate during the EMT process. Silencing of PLOD2 expression in breast cancer cells reduced succinate levels and inhibited cancer cell mesenchymal phenotypes and stemness, which was accompanied by elevated 5hmC levels in chromatin. Importantly, exogenous succinate rescued cancer cell stemness and 5hmC levels in PLOD2-silenced cells, suggesting that PLOD2 promotes cancer progression at least partially through succinate. These results reveal the previously unidentified function of succinate in enhancing cancer cell plasticity and stemness.

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The PLOD2/succinate axis regulates the epithelial–mesenchymal plasticity and cancer cell stemness

Abstract

Bibliographical note

Funding

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UN SDGs

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