Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation.
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.
Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA.
Min
M
Pan
Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA.
Michael A
MA
Reid
Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA.
Xazmin H
XH
Lowman
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA.|Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
Rajan P
RP
Kulkarni
Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA.
Thai Q
TQ
Tran
Department of Pharmacology and Cancer Biology, Duke University Medical School, Durham, North Carolina 27710, USA.
Xiaojing
X
Liu
Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA.
Ying
Y
Yang
Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA.
Jenny E
JE
Hernandez-Davies
Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA.
Kimberly K
KK
Rosales
Department of Information Sciences, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA.
Haiqing
H
Li
Division of Dermatology, Department of Medicine, David Geffen School of Medicine and Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California 90095, USA.
Willy
0000-0002-1426-7190
W
Hugo
Division of Dermatology, Department of Medicine, David Geffen School of Medicine and Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California 90095, USA.
Chunying
C
Song
Department of Pathology, University of California San Diego, La Jolla, California 92093, USA.
Xiangdong
X
Xu
Department of Diabetes and Metabolic Disease, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA.
Dustin E
DE
Schones
Department of Diabetes and Metabolic Disease, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA.
David K
DK
Ann
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Viviana
0000-0001-5868-348X
V
Gradinaru
Division of Dermatology, Department of Medicine, David Geffen School of Medicine and Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California 90095, USA.
Roger S
RS
Lo
Department of Pharmacology and Cancer Biology, Duke University Medical School, Durham, North Carolina 27710, USA.
Jason W
0000-0002-7766-3502
JW
Locasale
Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA.
Mei
M
Kong
D000818:Animals; D019175:DNA Methylation / Q000502:physiology*; D005973:Glutamine / Q000172:deficiency / Q000378:metabolism; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007656:Ketoglutaric Acids / Q000378:metabolism; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*
D006657:Histones; D007656:Ketoglutaric Acids; D005973:Glutamine; D056466:Histone Demethylases; D008780:Methyltransferases