@article{4a256556f4f84acab3072f533eaa6974,
title = "2-Hydroxyglutarate destabilizes chromatin regulatory landscape and lineage fidelity to promote cellular heterogeneity",
abstract = "The epigenome delineates lineage-specific transcriptional programs and restricts cell plasticity to prevent non-physiological cell fate transitions. Although cell diversification fosters tumor evolution and therapy resistance, upstream mechanisms that regulate the stability and plasticity of the cancer epigenome remain elusive. Here we show that 2-hydroxyglutarate (2HG) not only suppresses DNA repair but also mediates the high-plasticity chromatin landscape. A combination of single-cell epigenomics and multi-omics approaches demonstrates that 2HG disarranges otherwise well-preserved stable nucleosome positioning and promotes cell-to-cell variability. 2HG induces loss of motif accessibility to the luminal-defining transcriptional factors FOXA1, FOXP1, and GATA3 and a shift from luminal to basal-like gene expression. Breast tumors with high 2HG exhibit enhanced heterogeneity with undifferentiated epigenomic signatures linked to adverse prognosis. Further, ascorbate-2-phosphate (A2P) eradicates heterogeneity and impairs growth of high 2HG-producing breast cancer cells. These findings suggest 2HG as a key determinant of cancer plasticity and provide a rational strategy to counteract tumor cell evolution.",
keywords = "2-hydroxyglutarate, DNA repair, breast cancer, cancer cell plasticity, chromatin CyTOF, epigenome fluctuation, lineage fidelity, luminal-to-basal transition, oncometabolite, single-cell epigenomics",
author = "Meena Kusi and Maryam Zand and Lin, {Li Ling} and Meizhen Chen and Anthony Lopez and Lin, {Chun Lin} and Wang, {Chiou Miin} and Lucio, {Nicholas D.} and Kirma, {Nameer B.} and Jianhua Ruan and Huang, {Tim H.M.} and Kohzoh Mitsuya",
note = "Funding Information: We thank all laboratory members for helpful discussions and technical assistance. We are grateful to the BioAnalytics and Single-Cell Core (BASiC) for single-cell analysis, the Mass Spectrometry Core for metabolite mass spectrometry, the Optical Imaging Facility for confocal imaging, the Flow Cytometry Shared Resource Facility at the University of Texas Health Science Center at San Antonio for flow cytometry, and the Northwestern Proteomics Core Facility for proteomics analyses. Sequencing data were generated in the Genome Sequencing Facility, which is supported by UT Health San Antonio, NIH-NCI P30 CA054174 (Mays Cancer Center at UT Health San Antonio), NIH Shared Instrument grant 1S10OD021805-01 (S10 grant), and Cancer Prevention and Research Institute of Texas (CPRIT) Core Facility Award RP160732. This study was supported by NIH grants U54 CA217297 and P30 CA054174 and CPRIT grant RP150600. J.R. acknowledges funding from the US National Science Foundation (ABI 1565076). M.K. is a recipient of the CPRIT predoctoral fellowship (RP170345). T.H.-M.H. K.M. and M.K. jointly conceived the project, designed the experiments, interpreted the results, and prepared the manuscript with contributions from all co-authors. M.K. carried out the majority of the experiments and data analyses. J.R. M.Z. and C.-L.L. assisted with scATAC-seq data analysis, computational modeling, and statistical methods. M.K. A.L. and K.M. performed RNA-seq experiments and data analysis. K.M. and M.K. established the methods for chromatin CyTOF. L.-L.L. and M.C. conducted IncuCyte cell proliferation assays and CyTOF single-cell profiling. C.-M.W. N.D.L. and N.B.K. assisted with validation of metal-tagged antibodies. The authors declare no competing interests. Funding Information: We thank all laboratory members for helpful discussions and technical assistance. We are grateful to the BioAnalytics and Single-Cell Core (BASiC) for single-cell analysis, the Mass Spectrometry Core for metabolite mass spectrometry, the Optical Imaging Facility for confocal imaging, the Flow Cytometry Shared Resource Facility at the University of Texas Health Science Center at San Antonio for flow cytometry, and the Northwestern Proteomics Core Facility for proteomics analyses. Sequencing data were generated in the Genome Sequencing Facility, which is supported by UT Health San Antonio, NIH-NCI P30 CA054174 (Mays Cancer Center at UT Health San Antonio), NIH Shared Instrument grant 1S10OD021805-01 (S10 grant), and Cancer Prevention and Research Institute of Texas (CPRIT) Core Facility Award RP160732. This study was supported by NIH grants U54 CA217297 and P30 CA054174 and CPRIT grant RP150600 . J.R. acknowledges funding from the US National Science Foundation ( ABI 1565076 ). M.K. is a recipient of the CPRIT predoctoral fellowship (RP170345). Publisher Copyright: {\textcopyright} 2021",
year = "2022",
month = jan,
day = "11",
doi = "10.1016/j.celrep.2021.110220",
language = "English (US)",
volume = "38",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "2",
}