CDX2 inducible microRNAs sustain colon cancer by targeting multiple DNA damage response pathway factors.
Fiche publication
Date publication
juillet 2021
Journal
Journal of cell science
Auteurs
Membres identifiés du Cancéropôle Est :
Dr FREUND Jean-Noël, Dr GROSS Isabelle
Tous les auteurs :
Priya S, Kaur E, Kulshrestha S, Pandit A, Gross I, Kumar N, Agarwal H, Khan A, Shyam R, Bhagat P, Prabhu JS, Nagarajan P, Deo SVS, Bajaj A, Freund JN, Mukhopadhyay A, Sengupta S
Lien Pubmed
Résumé
Meta-analysis of transcripts in colon adenocarcinoma patient tissues led to the identification of a DNA damage responsive miR signature called DNA damage sensitive miRs (DDSMs). DDSMs were experimentally validated in the cancerous colon tissues obtained from an independent cohort of colon cancer patients and in multiple cellular systems with high levels of endogenous DNA damage. All the tested DDSMs were transcriptionally upregulated by a common intestine-specific transcription factor, CDX2. Reciprocally, DDSMs were repressed via the recruitment of HDAC1/2 containing complexes onto the CDX2 promoter. These miRs downregulated multiple key targets in the DNA damage response (DDR) pathway, namely BRCA1, ATM, Chk1 and RNF8. CDX2 directly regulated the DDSMs which led to increased tumor volume and metastasis in multiple preclinical models. In colon cancer patient tissues the DDSMs negatively correlated with BRCA1 levels, were associated with decreased probability of survival, and thereby could be used as a prognostic biomarker.
Mots clés
ATM, BLM, BRCA1, Chk1, Colon cancer, DNA damage response, DNA repair, MicroRNA, RNF8
Référence
J Cell Sci. 2021 Jul 19;: