Abstract A15: Sin3B: a non-classical tumor suppressor

Abstract

Abstract Perturbations in cell cycle regulators elicit hyperproliferation and the inability of cells to exit the cell cycle, which are common occurrences in cancer. Recently, we have demonstrated that Sin3B, an essential component of the mammalian histone deacetylase repressor complex, is required for oncogene-induced senescence both in vitro and in vivo. Surprisingly, primary Sin3B-null cells are not readily transformed upon ectopic expression of oncogenic Ras. Thus, these observations indicate that loss of Sin3B uncouples the ability to undergo senescence from the sensitivity to transformation in primary cells. To better understand the relationship between Sin3B, senescence and transformation, we have generated novel immortalized cell lines genetically inactivated for Sin3B. Our results indicate that in these Sin3B-deleted cells, expression of oncogenic Ras promotes transformation and provides a proliferative advantage. Interestingly, we have demonstrated that the paired amphipathic helix 2 (PAH2) domain is crucial for the tumor suppressive nature of Sin3B. To elucidate the molecular bases for these effects, immunoprecipitation and mass-spectrometry was performed to identify the proteins associated with Sin3B and its loss-of-function mutants. We have now identified novel interactors of the Sin3B complex and defined crucial domains responsible for the complex's assembly. These observations suggest that Sin3B functions as a non-classical tumor suppressor which serves to limit the transformative potential of cancer cells. The restoration of Sin3B functionality and downstream pathways may prove useful in the design of targeted therapies to treat advanced disease. Citation Format: Anthony J. Bainor, Beatrix Ueberheide, Gregory David. Sin3B: a non-classical tumor suppressor. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr A15.