HDAC5 modulates SATB1 transcriptional activity to promote lung adenocarcinoma
Menée in vitro et à l'aide de xénogreffes d'adénocarcinome du poumon, cette étude met en évidence un mécanisme par lequel l'histone désacétylase HDAC5, en désacétylant le facteur de transcription SATB1, favorise la tumorigenèse
Background : Dysregulation of histone deacetylases has been linked to diverse cancers. HDAC5 is a histone deacetylase belonging to Class IIa family of histone deacetylases. Limited substrate repertoire restricts the understanding of molecular mechanisms underlying its role in tumorigenesis. Methods : We employed a biochemical screen to identify SATB1 as HDAC5-interacting protein. Coimmunoprecipitation and deacetylation assay were performed to validate SATB1 as a HDAC5 substrate. Proliferation, migration assay and xenograft studies were performed to determine the effect of HDAC5-SATB1 interaction on tumorigenesis. Results : Here we report that HDAC5 binds to and deacetylates SATB1 at the conserved lysine 411 residue. Furthermore, dynamic regulation of acetylation at this site is determined by TIP60 acetyltransferase. We also established that HDAC5-mediated deacetylation is critical for SATB1-dependent downregulation of key tumor suppressor genes. Deacetylated SATB1 also represses SDHA-induced epigenetic remodeling and anti-proliferative transcriptional program. Thus, SATB1 spurs malignant phenotype in a HDAC5-dependent manner. Conclusions : Our study highlights the pivotal role of HDAC5 in tumorigenesis. Our findings provide key insights into molecular mechanisms underlying SATB1 promoted tumor growth and metastasis.