Heat Shock Factor 1 Epigenetically Stimulates Glutaminase-1-Dependent mTOR Activation to Promote Colorectal Carcinogenesis
Heat Shock Factor 1 Epigenetically Stimulates Glutaminase-1-Dependent mTOR Activation to Promote Colorectal Carcinogenesis
复制标题
热休克因子 1 表观遗传刺激谷氨酰胺酶 1 依赖性 mTOR 激活，促进结直肠癌发生
DOI：
10.1016/j.ymthe.2018.04.014
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发表时间：
2018-07-05
影响因子：
12.4
通讯作者：
Jin, Hongchuan
中科院分区：
文献类型：
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作者：
Li, Jiaqiu;Song, Ping;Jin, Hongchuan
热休克因子1（HSF 1）通常在应力条件下表现出其特性。在肿瘤中，HSF 1在调节癌细胞的生长、存活和侵袭性方面具有多效性特征。在这项研究中，我们发现HSF 1在结直肠癌（CRC）中表达增加，并与较短的无病生存期（DFS）呈正相关。CRC细胞中HSF 1的敲低减弱了它们的生长，同时抑制mTOR活化和谷氨酰胺代谢。HSF 1抑制靶向GLS 1（谷氨酰胺酶1）的microRNA 137（MIR 137）的表达，从而刺激GLS 1蛋白表达，促进谷氨酰胺分解和mTOR活化。HSF 1结合DNA甲基转移酶DNMT 3a并将其募集到lncRNA MIR 137宿主基因（MIR 137 HG）的启动子，抑制原代MIR 137的产生。HSF 1的化学抑制剂也在体外降低细胞生长，增加细胞凋亡，并损害谷氨酰胺代谢。此外，HSF 1的化学抑制和基因敲除均成功地增加了MIR 137的表达，降低了GLS 1的表达，并减轻了氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）小鼠的结直肠肿瘤发生。结论：HSF 1表达增高与结直肠癌预后不良有关。通过募集DNMT 3a来抑制靶向GLS 1 mRNA的MIR 137的表达，HSF 1刺激GLS 1依赖的mTOR激活以促进结直肠癌的发生。因此，靶向HSF 1以减弱氨解和mTOR活化可能是CRC治疗的有希望的方法。
Heat shock factor 1 (HSF1) generally exhibits its properties under stress conditions. In tumors, HSF1 has a pleiotropic feature in regulating growth, survival, and aggressiveness of cancer cells. In this study, we found HSF1 was increased in colorectal cancer (CRC) and had a positive correlation with shorter disease-free survival (DFS). Knockdown of HSF1 in CRC cells attenuated their growth while inhibiting mTOR activation and glutamine metabolism. HSF1 inhibited the expression of microRNA137 (MIR137), which targeted GLS1 (glutaminase 1), thus stimulating GLS1 protein expression to promote glutaminolysis and mTOR activation. HSF1 bound DNA methyltransferase DNMT3a and recruited it to the promoter of lncRNA MIR137 host gene (MIR137HG), suppressing the generation of primary MIR137. The chemical inhibitor of HSF1 also reduced cell growth, increased apoptosis, and impaired glutamine metabolism in vitro. Moreover, both chemical inhibition and genetic knockout of HSF1 succeeded in increasing MIR137 expression, reducing GLS1 expression, and alleviating colorectal tumorigenesis in azoxymethane (AOM)/dextran sulfate sodium (DSS) mice. In conclusion, HSF1 expression was increased and associated-with poor prognosis inCRC. By recruitingDNMT3a to suppress the expression of MIR137 that targets GLS1 mRNA, HSF1 stimulated GLS1-dependent mTOR activation to promote colorectal carcinogenesis. Therefore, targeting HSF1 to attenuate glutaminolysis and mTOR activation could be a promising approach for CRC treatment.