Targeting histone deacetylase SIRT1 in medulloblastoma

Summary Silent mating-type Information Regulation Two homology 1 (SIRT1) is the founding member of the Class III NAD+-dependent histone deacetylases and plays critical roles in a variety of cellular processes, including aging, homeostasis, metabolism, and stress response. Importantly, increasing evidence shows that, by deacetylating both histone and non-histone proteins, SIRT1 is involved in the initiation and progression of cancer. The proposed project is significant because despite the surge of interest in SIRT1 over the past two decades, there are still many knowledge gaps of exactly how SIRT1 works in tumorigenesis. The objective of this resubmission application is to advance our understanding of the novel function of SIRT1 and its implication in cancer. Aims 1 and 2 are designed to define the molecular mechanisms of SIRT1 in regulating centrosomal and ciliary biogenesis through the deacetylation of Polo-Like Kinase 2 (PLK2) and Coiled-Coil Domain- Containing protein 66 (CCDC66). A series of posttranslational modification events will be delineated to dissect how SIRT1 coordinates with cellular regulatory machineries and signaling pathways to tempo-spatially control centrosomal and ciliary biogenesis and function. In Aim 3, we will explore the therapeutic potential of manipulating SIRT1 activity and signaling to repress the in vitro and in vivo growth of sonic hedgehog (SHH) subtype medulloblastoma, a cancer subtype in which abnormal centrosomal/ciliary biogenesis and function are highly implicated. The results of this work will accelerate the fundamental understanding of an under-explored yet critical function of SIRT1 in cancer. More importantly, the expected outcome will yield new insight into the development of novel therapeutic approaches for difficult-to-treat cancers, such as SHH-medulloblastoma.