Abstract
The SIN3A-HDAC complex is a master transcriptional repressor, required for development but often deregulated in disease. Here, we report that the recently identified new component of this complex, SINHCAF/FAM60A, links the SIN3A-HDAC co-repressor complex function to the hypoxia response. SINHCAF Chromatin Immunoprecipitation-sequencing and gene expression analysis reveal a signature associated with the activation of the hypoxia response. We show that SINHCAF specifically repress HIF 2α mRNA and protein expression resulting in functional cellular changes in angiogenesis in-vitro, and proliferation in a range of cancer cell lines. Analysis of patient datasets demonstrates that SINHCAF and HIF 2α mRNA levels are inversely correlated and predict contrasting outcomes for patient survival in both colon and lung cancer. In an independent panel of samples from colon cancer patients SINHCAF, HIF 2α and the HIF 2α-target, Cited-2 are found to be inversely correlated. This relationship is also observed in a mouse model of colon cancer, indicating an evolutionary conserved mechanism. Our analysis reveals an expected link between SINHCAF and cancer cell signalling via regulation of the hypoxia response that is predictive of poor patient outcome. Furthermore, we demonstrate that SINHCAF is a putative biomarkers for colorectal and lung cancer, and anticipate that SINHCAF will be valid predictor for outcome in multiple disease processes.
Footnotes
e-mail addresses of all authors: John Biddlestone: j.biddlestone{at}dundee.ac.uk Michael Batie: m.t.batie{at}dundee.ac.uk Alena Shmakova: a.shmakova{at}dundee.ac.uk Daniel Bandarra: danielbandarra{at}gmail.com Elena Knatko: e.knatko{at}dundee.ac.uk Albena Dinkova-Kostova: A.DinkovaKostova{at}dundee.ac.uk Ivan Munoz: i.munoz{at}dundee.ac.uk Ramasubramanian Sundaramoorthy: R.Z.Sundaramoorthy{at}dundee.ac.uk Tom Owen-Hughes: t.a.owenhughes{at}dundee.ac.uk Sonia Rocha: srocha{at}liverpool.ac.uk