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Published October 2016 | Supplemental Material + Accepted Version
Journal Article Open

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

Abstract

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.

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.

Attached Files

Accepted Version - nihms865613.pdf

Supplemental Material - ncb3410-s1.pdf

Supplemental Material - ncb3410-s2.xlsx

Supplemental Material - ncb3410-s3.xlsx

Supplemental Material - ncb3410-s4.xlsx

Supplemental Material - ncb3410-s5.xlsx

Supplemental Material - ncb3410-sf1.jpg

Supplemental Material - ncb3410-sf2.jpg

Supplemental Material - ncb3410-sf3.jpg

Supplemental Material - ncb3410-sf4.jpg

Supplemental Material - ncb3410-sf5.jpg

Supplemental Material - ncb3410-sf6.jpg

Supplemental Material - ncb3410-sf7.jpg

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Created:
August 20, 2023
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