SIRT1-mediated expression of CD24 and epigenetic suppression of novel tumor suppressor MiR-1185-1 increases colorectal cancer stemness
Journal
Cancer Research
Journal Volume
80
Journal Issue
23
Pages
5257-5269
Date Issued
2020
Author(s)
Abstract
NAD-dependent deacetylase sirtuin-1 (SIRT1) is a class III histone deacetylase that positively regulates cancer-related pathways such as proliferation and stress resistance. SIRT1 has been shown to promote progression of colorectal cancer and is associated with cancer stemness, yet the precise mechanism between colorectal cancer stemness and SIRT1 remains to be further clarified. Here we report that SIRT1 signaling regulates colorectal cancer stemness by enhancing expression of CD24, a colorectal cancer stemness promoter. A novel miRNA, miR-1185-1, suppressed the expression of CD24 by targeting its 30UTR (untranslated region) and could be inhibited by SIRT1 via histone deacetylation. Targeting SIRT1 by RNAi led to elevated H3 lysine 9 acetylation on the promoter region of miR-1185-1, which increased expression of miR-1185-1 and further repressed CD24 translation and colorectal cancer stemness. In a mouse xenograft model, overexpression of miR-1185-1 in colorectal cancer cells substantially reduced tumor growth. In addition, expression of miR-1185-1 was downregulated in human colorectal cancer tissues, whereas expression of CD24 was increased. In conclusion, this study not only demonstrates the essential roles of a SIRT1-miR-1185-1- CD24 axis in both colorectal cancer stemness properties and tumorigenesis but provides a potential therapeutic target for colorectal cancer treatment. ?2020 American Association for Cancer Research.
Subjects
beta catenin; BMI1 protein; breast cancer resistance protein; CD133 antigen; CD24 antigen; fluorouracil; histone deacetylase; histone H3; messenger RNA; microRNA; microRNA 1185 1; sirtuin 1; unclassified drug; 3' untranslated region; animal cell; animal experiment; animal model; animal tissue; Article; bioinformatics; cancer recurrence; cancer stem cell; cancer stemness; carcinogenesis; cell migration; clinical article; cohort analysis; colorectal cancer; colorectal cancer cell line; controlled study; deacetylation; down regulation; enzyme induction; epigenetics; gene expression; gene knockdown; gene overexpression; histone acetylation; human; human cell; human tissue; in vitro study; in vivo study; mouse; nonhuman; oncological parameters; predictive value; priority journal; promoter region; protein expression; RNA interference; RNA translation; stem cell self-renewal; transcription initiation site; transcriptomics; tumor growth; tumor volume; tumor xenograft; upregulation; Western blotting
SDGs
Other Subjects
beta catenin; BMI1 protein; breast cancer resistance protein; CD133 antigen; CD24 antigen; fluorouracil; histone deacetylase; histone H3; messenger RNA; microRNA; microRNA 1185 1; sirtuin 1; unclassified drug; 3' untranslated region; animal cell; animal experiment; animal model; animal tissue; Article; bioinformatics; cancer recurrence; cancer stem cell; cancer stemness; carcinogenesis; cell migration; clinical article; cohort analysis; colorectal cancer; colorectal cancer cell line; controlled study; deacetylation; down regulation; enzyme induction; epigenetics; gene expression; gene knockdown; gene overexpression; histone acetylation; human; human cell; human tissue; in vitro study; in vivo study; mouse; nonhuman; oncological parameters; predictive value; priority journal; promoter region; protein expression; RNA interference; RNA translation; stem cell self-renewal; transcription initiation site; transcriptomics; tumor growth; tumor volume; tumor xenograft; upregulation; Western blotting
Type
journal article