代谢和表观遗传重编程在癌症治疗抗性中起重要作用。然而,人们对它们的相互作用知之甚少。我们在这里报道TIGAR升高(TP53诱导的糖酵解和凋亡调节因子),抗氧化剂和葡萄糖代谢调节剂和致癌组蛋白甲基转移酶NSD2(核受体结合SET结构域蛋白2)的靶标,主要位于治疗抗性肿瘤细胞的细胞核中,在那里它刺激NSD2表达并提高整体H3K36me2标记。机械上,TIGAR直接与抗氧化剂主调节因子NRF2相互作用,并促进NRF2,H3K4me3甲基化酶MLL1的染色质募集和延伸Pol-II,以刺激新的(NSD2)和已建立的(NQO1/2,PRDX1和GSTM4)靶标的表达NRF2,与其酶活性无关。核TIGAR通过有效维持氧化还原稳态在体外和肿瘤中赋予癌细胞对化学疗法和激素疗法的抗性。此外,TIGAR的核积累与临床肿瘤中NSD2的表达呈正相关,并与不良生存率密切相关。这些发现定义了肿瘤治疗抗性的氧化还原再平衡中的核TIGAR介导的表观遗传自调节环。
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.