SINHCAF/FAM60A links SIN3A function to the hypoxia response and its levels are predictive of cancer patient survival

Biddlestone, J.; Batie, M.; Shmakova, A.; Bandarra, D.; Knatko, E. V.; Dinkova-Kostova, A. T.; Munoz, I.; Sundaramoorthy, R.; Owen-Hughes, T.; Rocha, S.

doi:10.1101/176032

bioRxiv · 10.1101/176032

SINHCAF/FAM60A links SIN3A function to the hypoxia response and its levels are predictive of cancer patient survival

Biddlestone, J.·Batie, M.·Shmakova, A.·Bandarra, D.·Knatko, E. V.·Dinkova-Kostova, A. T.·Munoz, I.·Sundaramoorthy, R.·Owen-Hughes, T.·Rocha, S.

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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 2 mRNA and protein expression resulting in functional cellular changes in in-vitro angiogenesis, and proliferation. Analysis of patient datasets demonstrates that SINHCAF and HIF 2 mRNA levels are inversely correlated and predict contrasting outcomes for patient survival in both colon and lung cancer. This relationship is also observed in a mouse model of colon cancer, indicating an evolutionary conserved mechanism. Our analysis reveals an unexpected link between SINHCAF and cancer cell signalling via regulation of the hypoxia response that is predictive of poor patient outcome.

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Biddlestone, J., Batie, M., Shmakova, A., Bandarra, D., Knatko, E. V., Dinkova-Kostova, A. T., Munoz, I., Sundaramoorthy, R., Owen-Hughes, T., Rocha, S.. 2017-08-14. SINHCAF/FAM60A links SIN3A function to the hypoxia response and its levels are predictive of cancer patient survival. https://doi.org/10.1101/176032

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