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.
Document Type
Article
Publication Date
5-2023
Digital Object Identifier (DOI)
https://doi.org/10.1073/pnas.2214942120
Funding Information
We are very grateful to Dr. Sendurai A. Mani for providing the HMLER cell line. The Markey Cancer Center Biospecimen and Tissue Procurement Shared Resource Facility provided assistance in tissue fixation and sectioning; the Flow Cytometry and Cell Sorting Shared Resource Facility 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.).
Repository Citation
Tong, Yuxin; Qi, Yifei; Xiong, Gaofeng; Li, Junyan; Scott, Timothy L.; Chen, Jie; He, Daheng; Li, Linzhang; Wang, Chi; Lane, Andrew N.; and Xu, Ren, "The PLOD2/succinate axis regulates the epithelial–mesenchymal plasticity and cancer cell stemness" (2023). Markey Cancer Center Faculty Publications. 409.
https://uknowledge.uky.edu/markey_facpub/409
Notes/Citation Information
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).