Nuclear TIGAR mediates an epigenetic and metabolic autoregulatory loop via NRF2 in cancer therapeutic resistance

Hong Wang; Qianqian Wang; Guodi Cai; Zhijian Duan; Zoann Nugent; Jie Huang; Jianwei Zheng; Alexander D. Borowsky; Jian Jian Li; Peiqing Liu; Hsing Jien Kung; Leigh Murphy; Hong Wu Chen; Junjian Wang

doi:10.1016/j.apsb.2021.10.015

Nuclear TIGAR mediates an epigenetic and metabolic autoregulatory loop via NRF2 in cancer therapeutic resistance

Hong Wang, Qianqian Wang, Guodi Cai, Zhijian Duan, Zoann Nugent, Jie Huang, Jianwei Zheng, Alexander D. Borowsky, Jian Jian Li, Peiqing Liu, Hsing Jien Kung, Leigh Murphy, Hong Wu Chen, Junjian Wang

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

Abstract

Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance. However, their interplays are poorly understood. We report here that elevated TIGAR (TP53-induced glycolysis and apoptosis regulator), an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2 (nuclear receptor binding SET domain protein 2), is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark. Mechanistically, TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2, H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new (NSD2) and established (NQO1/2, PRDX1 and GSTM4) targets of NRF2, independent of its enzymatic activity. Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis. In addition, nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival. These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.

Original language	English
Pages (from-to)	1871-1884
Number of pages	14
Journal	Acta Pharmaceutica Sinica B
Volume	12
Issue number	4
DOIs	https://doi.org/10.1016/j.apsb.2021.10.015
Publication status	Accepted/In press - 2021
Externally published	Yes

Keywords

Epigenetic reprogramming
Metabolism
NRF2
NSD2
Oxidative stress
Redox homeostasis
Therapeutic resistance
TIGAR

ASJC Scopus subject areas

Pharmacology, Toxicology and Pharmaceutics(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.apsb.2021.10.015

Cite this

Wang, H., Wang, Q., Cai, G., Duan, Z., Nugent, Z., Huang, J., Zheng, J., Borowsky, A. D., Li, J. J., Liu, P., Kung, H. J., Murphy, L., Chen, H. W., & Wang, J. (Accepted/In press). Nuclear TIGAR mediates an epigenetic and metabolic autoregulatory loop via NRF2 in cancer therapeutic resistance. Acta Pharmaceutica Sinica B, 12(4), 1871-1884. https://doi.org/10.1016/j.apsb.2021.10.015

@article{85ae0a55356c495db729dbec5ab4b669,

title = "Nuclear TIGAR mediates an epigenetic and metabolic autoregulatory loop via NRF2 in cancer therapeutic resistance",

abstract = "Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance. However, their interplays are poorly understood. We report here that elevated TIGAR (TP53-induced glycolysis and apoptosis regulator), an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2 (nuclear receptor binding SET domain protein 2), is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark. Mechanistically, TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2, H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new (NSD2) and established (NQO1/2, PRDX1 and GSTM4) targets of NRF2, independent of its enzymatic activity. Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis. In addition, nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival. These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.",

keywords = "Epigenetic reprogramming, Metabolism, NRF2, NSD2, Oxidative stress, Redox homeostasis, Therapeutic resistance, TIGAR",

author = "Hong Wang and Qianqian Wang and Guodi Cai and Zhijian Duan and Zoann Nugent and Jie Huang and Jianwei Zheng and Borowsky, {Alexander D.} and Li, {Jian Jian} and Peiqing Liu and Kung, {Hsing Jien} and Leigh Murphy and Chen, {Hong Wu} and Junjian Wang",

note = "Funding Information: We thank Dr. Robert Clarke and Dr. John Minna for providing the cells and Drs. Karen Vousden, Ah-Ng Kong, and Danna D. Zhang for providing plasmid constructs. This work was supported by the National Natural Science Foundation of China ( 81872891 ), the Guangdong Natural Science Funds for Distinguished Young Scholar (No. 2019B151502016 , China), Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program ( 2017BT01Y093 , China), National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province, 2017B090903004 , China), the Fundamental Research Funds for the Central Universities (No. 19ykzd23 , China). The Manitoba Breast Tumor Bank, a member of the Canadian Tissue Repository Network, was funded in part by the Cancer Care Manitoba Foundation ( CCMF , Canada) and previously the Canadian Institutes of Health Research (CIHR, PRG80155 , Canada). Publisher Copyright: {\textcopyright} 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences",

year = "2021",

doi = "10.1016/j.apsb.2021.10.015",

language = "English",

volume = "12",

pages = "1871--1884",

journal = "Acta Pharmaceutica Sinica B",

issn = "2211-3835",

publisher = "Chinese Academy of Medical Sciences",

number = "4",

}

TY - JOUR

T1 - Nuclear TIGAR mediates an epigenetic and metabolic autoregulatory loop via NRF2 in cancer therapeutic resistance

AU - Wang, Hong

AU - Wang, Qianqian

AU - Cai, Guodi

AU - Duan, Zhijian

AU - Nugent, Zoann

AU - Huang, Jie

AU - Zheng, Jianwei

AU - Borowsky, Alexander D.

AU - Li, Jian Jian

AU - Liu, Peiqing

AU - Kung, Hsing Jien

AU - Murphy, Leigh

AU - Chen, Hong Wu

AU - Wang, Junjian

N1 - Funding Information: We thank Dr. Robert Clarke and Dr. John Minna for providing the cells and Drs. Karen Vousden, Ah-Ng Kong, and Danna D. Zhang for providing plasmid constructs. This work was supported by the National Natural Science Foundation of China ( 81872891 ), the Guangdong Natural Science Funds for Distinguished Young Scholar (No. 2019B151502016 , China), Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program ( 2017BT01Y093 , China), National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province, 2017B090903004 , China), the Fundamental Research Funds for the Central Universities (No. 19ykzd23 , China). The Manitoba Breast Tumor Bank, a member of the Canadian Tissue Repository Network, was funded in part by the Cancer Care Manitoba Foundation ( CCMF , Canada) and previously the Canadian Institutes of Health Research (CIHR, PRG80155 , Canada). Publisher Copyright: © 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences

PY - 2021

Y1 - 2021

N2 - Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance. However, their interplays are poorly understood. We report here that elevated TIGAR (TP53-induced glycolysis and apoptosis regulator), an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2 (nuclear receptor binding SET domain protein 2), is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark. Mechanistically, TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2, H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new (NSD2) and established (NQO1/2, PRDX1 and GSTM4) targets of NRF2, independent of its enzymatic activity. Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis. In addition, nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival. These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.

AB - Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance. However, their interplays are poorly understood. We report here that elevated TIGAR (TP53-induced glycolysis and apoptosis regulator), an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2 (nuclear receptor binding SET domain protein 2), is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark. Mechanistically, TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2, H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new (NSD2) and established (NQO1/2, PRDX1 and GSTM4) targets of NRF2, independent of its enzymatic activity. Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis. In addition, nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival. These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.

KW - Epigenetic reprogramming

KW - Metabolism

KW - NRF2

KW - NSD2

KW - Oxidative stress

KW - Redox homeostasis

KW - Therapeutic resistance

KW - TIGAR

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U2 - 10.1016/j.apsb.2021.10.015

DO - 10.1016/j.apsb.2021.10.015

M3 - Article

AN - SCOPUS:85120868194

SN - 2211-3835

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EP - 1884

JO - Acta Pharmaceutica Sinica B

JF - Acta Pharmaceutica Sinica B

IS - 4

ER -

Nuclear TIGAR mediates an epigenetic and metabolic autoregulatory loop via NRF2 in cancer therapeutic resistance

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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