Open AccessConcerted functions of HDAC1 and microRNA‐574‐5p repress alternatively spliced ceramide synthase 1 expression in human cancer cells
Author(s) -
MeyersNeedham Marisa,
Ponnusamy Suriyan,
Gencer Salih,
Jiang Wenhui,
Thomas Raquela J.,
Senkal Can E.,
Ogretmen Besim
Publication year - 2012
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201100189
Subject(s) - ceramide , ceramide synthase , microrna , atp synthase , microbiology and biotechnology , hdac1 , cancer research , chemistry , biology , gene , genetics , apoptosis , histone , histone deacetylase
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.