Cellular senescence, a permanent cell cycle exit triggered by different stresses, has recently emerged as a safeguard mechanism against both uncontrolled proliferation and the accumulation of deleterious genetic alterations that occur during oncogenic transformation. Markers of cellular senescence have been identified in early stage human cancers, including preneoplastic prostate lesions, but are lost as the tumors progress. Consistent with a role of senescence in the prevention of tumor progression, genetic inactivation of essential components of the senescence pathway in mouse models leads to the acceleration of cancer progression. Despite accumulating evidence for its biological relevance in tumor suppression, the molecular bases underlying the establishment of cellular senescence remain largely elusive. Recently, the transcriptional silencing of pro-proliferative genes via heterochromatinization has been shown to correlate with the permanent senescence-associated cell cycle exit. Our preliminary results using genetically engineered mice and cells, demonstrate that the histone deacetylase (HDAC) associated Sin3B protein is required for both replicative and oncogene-induced cellular senescence. In addition, Sin3B is specifically induced upon oncogenic stress, and its overexpression is sufficient to induce cellular senescence in primary fibroblasts.
The specific aims of this proposal include the determination of the underlying molecular and cellular mechanisms by which Sin3B regulates senescence and prevent cancer progression in mammals. Specifically, we propose to identify the molecular events leading to Sin3B upregulation upon oncogenic stress, and determine how Sin3B upregulation induces cellular senescence (Aim 1);to investigate the contribution of Sin3B-induced senescence in the suppression of cellular transformation in fibroblasts (Aim 2);to test the hypothesis that Sin3B expression prevents prostate tumor progression in vivo (Aim 3). To do so, we will use a combination of molecular, cellular and biochemical approaches, as well as genetically engineered mouse models of cancer.

Public Health Relevance

Cellular senescence represents a driving force for aging as well as a barrier against cancer. We have identified Sin3B as a new and essential regulator of cellular senescence. Understanding the molecular basis for its role in the prevention of tumor progression has important implications for human health.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA148639-03
Application #
8408763
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Okano, Paul
Project Start
2011-01-01
Project End
2016-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
3
Fiscal Year
2013
Total Cost
$329,635
Indirect Cost
$134,585
Name
New York University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
DiMauro, T; Cantor, D J; Bainor, A J et al. (2015) Transcriptional repression of Sin3B by Bmi-1 prevents cellular senescence and is relieved by oncogene activation. Oncogene 34:4011-7
Rielland, Maïté; Cantor, David J; Graveline, Richard et al. (2014) Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression. J Clin Invest 124:2125-35
Jelinic, Petar; Pellegrino, Jessica; David, Gregory (2011) A novel mammalian complex containing Sin3B mitigates histone acetylation and RNA polymerase II progression within transcribed loci. Mol Cell Biol 31:54-62