MicroRNA-7 Compromises p53-dependent Apoptosis by Controlling the Expression of the Chromatin Remodeling Factor SMARCD1 [Signal Transduction]

November 5th, 2015 by Hong, C.-F., Lin, S.-Y., Chou, Y.-T., Wu, C.-W.

We previously demonstrated that EGFR upregulated miR-7 to promote tumor growth during lung cancer oncogenesis. Several lines of evidence have suggested that alterations in chromatin remodeling components contribute to cancer initiation and progression. In this study, we identified SMARCD1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, member 1) as a novel target gene of miR-7. miR-7 expression reduced SMARCD1 protein expression in lung cancer cell lines. We used luciferase reporters carrying wild type or mutated 3'UTR of SMARCD1, and found that miR-7 blocked SMARCD1 expression by binding to two seed regions in the 3'UTR of SMARCD1 and downregulated SMARCD1 mRNA expression. Additionally, upon chemotherapy drug treatment, miR-7 downregulated p53-dependent apoptosis-related gene BAX (BCL2-associated X protein) and p21 expression by interfering the interaction between SMARCD1 and p53, thereby reducing caspase3 cleavage and the downstream apoptosis cascades. We found that while SMARCD1 sensitized lung cancer cells to chemotherapy drug-induced apoptosis, miR-7 enhanced the drug resistance potential of lung cancer cells against chemotherapy drugs. SMARCD1 was downregulated in non-small cell lung cancer (NSCLC) patients and lung adenocarcinoma cell lines, and SMARCD1 and miR-7 expression levels were negatively correlated in clinical samples. Our investigation into the involvement of the EGFR-regulated miRNA pathway in the SWI/SNF chromatin remodeling complex suggest that EGFR-mediated miR-7 suppressed the coupling of the chromatin remodeling factor SMARCD1 with p53, resulting in increased chemo-resistance of lung cancer cells.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on MicroRNA-7 Compromises p53-dependent Apoptosis by Controlling the Expression of the Chromatin Remodeling Factor SMARCD1 [Signal Transduction]