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

EMBO Molecular Medicine

Marisa Meyers-Needham¹  Suriyan Ponnusamy¹  Salih Gencer¹  Wenhui Jiang¹  Raquela J. Thomas¹  Can E. Senkal¹ 

[1] Department of Biochemistry and Molecular Biology, Medical University of South Carolina, SC, USA

关键词: ceramide synthase 1;    lipid signalling;    sphingolipids;    sphingosine;    sphingosine 1‐phosphate;   

DOI  :  10.1002/emmm.201100189

来源: Wiley

【 摘 要 】

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 C₁₈-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 C₁₈-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.

【 授权许可】

Unknown   
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