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

Research output: Contribution to journalArticlepeer-review

127 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1090-1101
Number of pages12
JournalNature Cell Biology
Volume18
Issue number10
DOIs
StatePublished - Sep 28 2016
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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