Shen Qi, Wang Rui, Liu Xinling, Song Ping, Zheng Mingzhu, Ren Xiaomin, Ma Jingang, Lu Zhong, Li Jiaqiu
Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230002, China.
Department of Oncology, Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang 261031, China.
Cancers (Basel). 2022 Aug 9;14(16):3855. doi: 10.3390/cancers14163855.
Super enhancers are critical for the gene transcription responsible for cell fate by interacting with transcription factors. However, the relevance of HSF1 to super enhancers in tumors remains obscure. We profiled H3K27ac enrichment by chromatin immunoprecipitation sequencing. HSF1-mediated lncRNAs were identified by lncRNA microarray. The characteristics of LINC00857 were explored by in vitro and in vivo assays. The mechanism was studied via chromatin immunoprecipitation, RNA immunoprecipitation, and HSF1/ANXA11 knockout mice. We found that super enhancers occupied multiple gene loci in colorectal cancer. We screened out an HSF1-mediated super enhancer, lncRNA-LINC00857, which exerts its characteristics in promoting cell growth via regulating glutamine metabolism. Notably, HSF1 could stimulate the super-enhancer activity of LINC00857 by the enrichment of acetyltransferase P300 to its gene loci, contributing to LINC00857 transcription. In turn, nuclear LINC00857 cooperated with HSF1 to promote ANXA11 transcription, which modulated SLC1A5/ASCT2 protein expression by binding competitively to miR-122-5p. The knockout of ANXA11 attenuated colorectal cancer formation in vivo. Collectively, we shed light on a closely cooperative machinery between HSF1 and super enhancers. HSF1 could stimulate acetyltransferase P300-mediated super-enhancer activity to facilitate LINC00857 expression, contributing to SLC1A5-mediated glutamine transport. Targeting the HSF1/LINC00857/ANXA11 axis may provide a valuable therapeutic strategy against colorectal cancer.
超级增强子通过与转录因子相互作用，对决定细胞命运的基因转录至关重要。然而，HSF1在肿瘤中与超级增强子的相关性仍不清楚。我们通过染色质免疫沉淀测序分析了H3K27ac富集情况。通过lncRNA微阵列鉴定了HSF1介导的lncRNAs。通过体外和体内实验探究了LINC00857的特征。通过染色质免疫沉淀、RNA免疫沉淀和HSF1/ANXA11基因敲除小鼠研究了其机制。我们发现超级增强子占据了结直肠癌中的多个基因位点。我们筛选出一个HSF1介导的超级增强子lncRNA-LINC00857，它通过调节谷氨酰胺代谢促进细胞生长。值得注意的是，HSF1可通过将乙酰转移酶P300富集到其基因位点来刺激LINC00857的超级增强子活性，促进LINC00857转录。反过来，细胞核中的LINC00857与HSF1协同促进ANXA11转录，ANXA11通过竞争性结合miR-122-5p来调节SLC1A5/ASCT2蛋白表达。敲除ANXA11可在体内减弱结直肠癌的形成。总的来说，我们揭示了HSF1与超级增强子之间紧密协作的机制。HSF1可刺激乙酰转移酶P300介导的超级增强子活性以促进LINC00857表达，有助于SLC1A5介导的谷氨酰胺转运。靶向HSF1/LINC00857/ANXA11轴可能为结直肠癌提供一种有价值的治疗策略。
