Concerted functions of HDAC1 and microRNA-574-5p repress alternatively spliced ceramide synthase 1 expression in human cancer cells.

Abstract

Histone deacetylases (HDACs) and microRNAs (miRs) have pro-survival roles, but the mechanism behind this is unclear. Repression of ceramide synthase 1 (CerS1), altering C(18) -ceramide generation, was linked to drug resistance and metastasis. Here we report that the CerS1 promoter was repressed by HDAC1-dependent inhibition of Sp1 recruitment to two specific GC-boxes spanning the -177 and -139 region. Moreover, an alternatively spliced variant CerS1 mRNA (CerS1-2) was detected mainly in cancer cells or primary tumour tissues compared to controls, which was targeted by miR-574-5p for degradation. A specific 3'UTR-targeting site, localized within the retained intron between exons 6 and 7, was identified, and its mutation, or miR-574-5p knockdown prevented the degradation of CerS1-2 mRNA. Interference with HDAC1 and miR-574-5p reconstituted CerS1-2 expression and C(18) -ceramide generation in multiple human cancer cell lines, which subsequently inhibited proliferation and anchorage-independent growth. Accordingly, knockdown of CerS1 partially protected cancer cells from MS-275/miR-574-5p siRNA-mediated growth inhibition. Thus, these data suggest that the HDAC1/miR-574-5p axis might provide a novel therapeutic target to reconstitute tumour suppressor CerS1/ceramide signalling.

• Authors: Marisa Meyers-Needham, Suriyan Ponnusamy, Salih Gencer, Wenhui Jiang, Raquela J Thomas, Can E Senkal, Besim Ogretmen
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 4 Issue 2 Pg. 78-92 (Feb 2012) ISSN: 1757-4684 [Electronic] England
• PMID: 22180294 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 EMBO Molecular Medicine.

Chemical References

• 3' Untranslated Regions
• MIRN574 microRNA, human
• Membrane Proteins
• MicroRNAs
• Tumor Suppressor Proteins
• CERS1 protein, human
• CERS2 protein, human
• Sphingosine N-Acyltransferase
• HDAC1 protein, human
• Histone Deacetylase 1

Topics

• 3' Untranslated Regions
• Alternative Splicing
• Cell Line, Tumor
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Histone Deacetylase 1 (genetics)
• Humans
• Membrane Proteins (genetics, metabolism)
• MicroRNAs (genetics)
• Neoplasms (genetics, pathology)
• Signal Transduction (genetics)
• Sphingosine N-Acyltransferase (genetics, metabolism)
• Tumor Suppressor Proteins (genetics, metabolism)