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Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation

Pan, Min and Reid, Michael A. and Lowman, Xazmin H. and Kulkarni, Rajan P. and Tran, Thai Q. and Liu, Xiaojing and Yang, Ying and Hernandez-Davies, Jenny E. and Rosales, Kimberly K. and Li, Haiqing and Hugo, Willy and Song, Chunying and Xu, Xiangdong and Schones, Dustin E. and Ann, David K. and Gradinaru, Viviana and Lo, Roger S. and Locasale, Jason W. and Kong, Mei (2016) Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nature Cell Biology, 18 (10). pp. 1090-1101. ISSN 1465-7392. PMCID PMC5536113. doi:10.1038/ncb3410.

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[img] Image (JPEG) (Supplementary Figure 1: Tumour core regions display heterogeneity) - Supplemental Material
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[img] Image (JPEG) (Supplementary Figure 2: Histone methylation in low glutamine is not due to low proliferation rate of cells) - Supplemental Material
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[img] Image (JPEG) (Supplementary Figure 3: Low glutamine is the major driver of histone methylation) - Supplemental Material
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[img] Image (JPEG) (Supplementary Figure 4: Low glutamine induces suppression of differentiation genes, which can be reversed by EPZ005687) - Supplemental Material
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[img] Image (JPEG) (Supplementary Figure 5: Low glutamine-induced differential gene expression is reversed by H3K27me3 inhibitor) - Supplemental Material
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[img] Image (JPEG) (Supplementary Figure 7: Neither HIF-1α nor DNA methylation is involved in low glutamine-induced epigenetic modification) - Supplemental Material
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Poorly organized tumour vasculature often results in areas of limited nutrient supply and hypoxia. Despite our understanding of solid tumour responses to hypoxia, how nutrient deprivation regionally affects tumour growth and therapeutic response is poorly understood. Here, we show that the core region of solid tumours displayed glutamine deficiency compared with other amino acids. Low glutamine in tumour core regions led to dramatic histone hypermethylation due to decreased α-ketoglutarate levels, a key cofactor for the Jumonji-domain-containing histone demethylases. Using patient-derived ^(V600E)BRAF melanoma cells, we found that low-glutamine-induced histone hypermethylation resulted in cancer cell dedifferentiation and resistance to BRAF inhibitor treatment, which was largely mediated by methylation on H3K27, as knockdown of the H3K27-specific demethylase KDM6B and the methyltransferase EZH2 respectively reproduced and attenuated the low-glutamine effects in vitro and in vivo. Thus, intratumoral regional variation in the nutritional microenvironment contributes to tumour heterogeneity and therapeutic response.

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URLURL TypeDescription ReadCube Access CentralArticle
Gradinaru, Viviana0000-0001-5868-348X
Locasale, Jason W.0000-0002-7766-3502
Alternate Title:Regional Glutamine Deficiency in Tumours Promotes De-differentiation through Inhibition of Histone Demethylation
Additional Information:© 2016 Macmillan Publishers Limited. Received 5 May 2016; accepted 12 August 2016; published online 12 September 2016. We thank members of the Kong laboratory for helpful comments on the manuscript. This work was supported by National Institutes of Health (NIH)/National Cancer Institute (NCI) grant R01CA183989 (to M.K.), Caltech-City of Hope Biomedical Initiative Pilot Grant (to M.K. and V.G.), American Cancer Society Research Scholar RSG-16-085-01-TBE (to M.K.) and Stand up to Cancer Philip A. Sharp Innovation in Collaboration Award. M.K. is the Pew Scholar in the Biomedical Sciences and the V scholar in Cancer Research. X.H.L. is supported by the DNA Damage Response and Oncogenic Signaling (DDROS) Training Program at City of Hope. Research reported here includes work carried out in Core Facilities supported by the NIH/NCI under grant number P30CA33572. Author Contributions: M.P. designed and performed most of the experiments, analysed and interpreted the data and wrote the manuscript. M.K. conceived and supervised this study, designed experiments and wrote the paper. M.A.R. and X.H.L. helped to measure metabolites and assisted with mouse experiments. R.P.K. and V.G. performed PACT experiments. T.Q.T. assisted with flow cytometry experiments. Y.Y. assisted with qPCR experiments. J.E.H.-D. and K.K.R. helped set up melanoma cell culture. W.H., C.S. and R.S.L. provided patient-derived melanoma cells and conceptual advice on melanoma dedifferentiation. X.X. assisted with IHC experiments. D.E.S. assisted with ChIP experiments and H.L. performed the bioinformatics analyses. D.K.A. provided conceptual advice on hypoxia and metabolism experiments. X.L. and J.W.L. performed and helped to analyse the metabolomics experiments. The authors declare no competing financial interests.
Funding AgencyGrant Number
Caltech-City of Hope Biomedical InitiativeUNSPECIFIED
American Cancer SocietyRSG-16-085-01-TBE
Stand up to CancerUNSPECIFIED
Pew Charitable TrustUNSPECIFIED
V Foundation for Cancer ResearchUNSPECIFIED
Issue or Number:10
PubMed Central ID:PMC5536113
Record Number:CaltechAUTHORS:20160920-092113773
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Official Citation:Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation Min Pan, Michael A. Reid, Xazmin H. Lowman, Rajan P. Kulkarni, Thai Q. Tran, Xiaojing Liu, Ying Yang, Jenny E. Hernandez-Davies, Kimberly K. Rosales, Haiqing Li, Willy Hugo, Chunying Song, Xiangdong Xu, Dustin E. Schones, David K. Ann, Viviana Gradinaru, Roger S. Lo, Jason W. Locasale & Mei Kong Nature Cell Biology 18, 1090–1101 (2016) doi:10.1038/ncb3410
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:70456
Deposited By: Tony Diaz
Deposited On:21 Sep 2016 17:13
Last Modified:19 Apr 2022 17:06

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