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A CtBP‐miRNA network links metabolism with the acquisition of stem cell traits and drug resistance (59.4)
Author(s) -
Byun Jung,
Gardner Kevin
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.59.4
Subject(s) - microrna , epigenetics , biology , chromatin , regulation of gene expression , gene expression , regulator , microbiology and biotechnology , gene , cancer research , genetics
One of the most common causes of mortality in breast cancer is recurrence and/or the development of resistance to chemotherapy. In particular the acquisition of multiple drug resistance (MDR) has posed one of the greatest challenges in treating breast cancer. Recent findings indicate that some forms of drug resistance can be regulated by microRNAs (miRNAs), a relatively newly described class of non‐coding genes that can dramatically influence gene expression by controlling mRNA degradation and/or translation inhibition. This has led to numerous pre‐clinical therapeutic strategies to modulate or reverse drug resistance by miRNA targeting. The C‐terminal binding protein (CTBP) is an epigenetic regulator that is activated in the presence of NADH to recruit and target a variety of histone modifying complexes and transcriptional regulators to chromatin, thus providing a defined mechanism through which carbohydrate metabolism can drive epigenetic regulatory events. We have recently shown that CtBP drives epithelial mesenchymal transition (EMT), genome instability, and the acquisition of stem cell tumor‐initiating cell‐like pathways in breast cancer. Interestingly we find that CTBP also directly targets and inhibits miR‐Let7i expression, a central regulator of cellular pluripotency that downregulates major drivers of pluripotency including Lin28, and HMG2a. miR‐Let7i also represses expression of the IGF2BP1,2,3 proteins that stabilize the mRNA transcripts of HRAS, MYC and MDR1 . Moreover, it has also been recently shown that miR‐137 inhibits CtBP expression. This surprising confluence of pathways suggest a regulatory CtBP‐miR network in which CtBP and miR‐ Let7i act as major hubs that provide means through which metabolic imbalance can influence both the acquisition of drug resistance and tumor‐initiating cell like properties.