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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Pan, M; Reid, MA; Lowman, XH; Kulkarni, RP; Tran, TQ; Liu, X; Yang, Y; Hernandez-Davies, JE; Rosales, KK; Li, H; Hugo, W; Song, C; Xu, X; Schones, DE; Ann, DK; Gradinaru, V; Lo, RS; Locasale, JW; Kong, M

Published Date

  • October 2016

Published In

Volume / Issue

  • 18 / 10

Start / End Page

  • 1090 - 1101

PubMed ID

  • 27617932

Pubmed Central ID

  • 27617932

Electronic International Standard Serial Number (EISSN)

  • 1476-4679

Digital Object Identifier (DOI)

  • 10.1038/ncb3410

Language

  • eng

Conference Location

  • England