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

Acta Pharm Sin B. 2022 Apr;12(4):1871-1884. doi: 10.1016/j.apsb.2021.10.015. Epub 2021 Oct 21.

Authors

Hong Wang¹, Qianqian Wang¹, Guodi Cai¹, Zhijian Duan², Zoann Nugent³, Jie Huang⁴, Jianwei Zheng¹, Alexander D Borowsky⁵, Jian Jian Li⁶, Peiqing Liu^{1

7}, Hsing-Jien Kung^{2

8}, Leigh Murphy³, Hong-Wu Chen^{2

8}, Junjian Wang^{1

7}

Affiliations

¹ School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
² Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA 95817, USA.
³ Research Institute in Oncology and Hematology, University of Manitoba and CancerCare Manitoba, Winnipeg R3E 0V9, Canada.
⁴ Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
⁵ Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA 95817, USA.
⁶ Department of Radiation Oncology, University of California, Davis, Sacramento, CA 95817, USA.
⁷ National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China.
⁸ UC Davis Comprehensive Cancer Center, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.

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: ARE, antioxidant response element; DoxR, doxorubicin resistant; Epigenetic reprogramming; F2,6bPase, fructose-2,6-bisphosphatase; FBS, fetal bovine serum; Metabolism; NLS, nuclear localization signal; NRF2; NRF2, NF-E2-related factor-2; NSCLC, non-small-cell lung carcinoma; NSD2; NSD2, nuclear receptor binding SET domain protein 2; Oxidative stress; PGC1α, PPARG coactivator 1 alpha; PPP, pentose phosphate pathway; RadR, ionizing radiation-resistance; Redox homeostasis; TIGAR; TIGAR, TP53-induced glycolysis and apoptosis regulator; TamR, tamoxifen resistant; Therapeutic resistance.