Pan-cancer analysis of enhancer-induced MIR17HG and validation as a SIRT1-promoting factor in colorectal cancer

MIR17HG plays a significant role in malignancies. Here, we explore its oncogenic roles across cancers. We further revealed the upstream and downstream regulatory mechanisms of MIR17HG in colorectal cancer. Through bioinformatics analysis, we found that 23 tumor types presented higher MIR17HG expression levels than normal tissues did, and 11 tumor types presented lower MIR17HG expression levels. MIR17HG expression is closely related to tumor stage and prognosis. Single-cell sequencing data analysis revealed that MIR17HG is highly expressed in the tumor microenvironment. MIR17HG expression is correlated with a cold immune microenvironment, including immune scores, immune cell infiltration and immune checkpoint gene expression. More importantly, patients with high MIR17HG expression are inclined to have worse immunotherapy effects. Targeting MIR17HG could weaken SIRT1-mediated cell survival in colorectal cancer. Many sensitive drugs are screened out for the SIRT1 protein by sensitivity analysis and virtual screening. Notably, the transcription factor HSF1 stimulates acetyltransferase P300-mediated enhancer activity in the MIR17HG promoter region, thereby activating MIR17HG transcription. Furthermore, clinical and mouse samples revealed the co-expression of the HSF1/SIRT1 axis in colorectal cancer. Overall, MIR17HG has the potential to be a bona fide biomarker for tumor diagnosis and predicting immunotherapy efficacy. Targeting the HSF1/MIR17HG/SIRT1 axis may be helpful for the treatment of colorectal cancer. We identify HSF1-mediated enhancer activity as a novel driver of MIR17HG overexpression, promoting SIRT1-dependent colorectal cancer progression.