Sin3B Expression Is Required for Cellular Senescence and Is Up-regulated upon Oncogenic Stress

Abstract

Serial passage of primary mammalian cells or strong mitogenic signals induce a permanent exit from the cell cycle called senescence. A characteristic of senescent cells is the heterochromatinization of loci encoding pro-proliferative genes, leading to their transcriptional silencing. Senescence is thought to represent a defense mechanism against uncontrolled proliferation and cancer. Consequently, genetic alterations that allow senescence bypass are associated with susceptibility to oncogenic transformation. We show that fibroblasts genetically inactivated for the chromatin-associated Sin3B protein are refractory to replicative and oncogene-induced senescence. Conversely, overexpression of Sin3B triggers senescence and the formation of senescence-associated heterochromatic foci. Although Sin3B is strongly up-regulated upon oncogenic stress, decrease in expression of Sin3B is associated with tumor progression in vivo, suggesting that expression of Sin3B may represent a barrier against transformation. Together, these results underscore the contribution of senescence in tumor suppression and suggest that expression of chromatin modifiers is modulated at specific stages of cellular transformation. Consequently, these findings suggest that modulation of Sin3B-associated activities may represent new therapeutic opportunities for treatment of cancers. [Cancer Res 2009;69(16):6430-7]

Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression

“…SIN3B was scarcely detected in control human pancreas and PDAC sections, but was strongly upregulated in both pancreatitis and PanINs, consistent with our previous observations in mouse tissues ( Figure 6A) (34). Interestingly, in most samples with high levels of SIN3B expression, we also observed p-STAT3 and IL-1α positivity, specifically at the sites of ADM and in PanIN lesions ( Figure 6A).…”

“…Our recent discovery that the chromatin modifier SIN3B mediates RAS-induced senescence in mouse fibroblasts coupled with our observation that SIN3B is upregulated in RASdriven PanINs initially hinted toward a tumor-suppressive role for SIN3B in the pancreas (34). We demonstrate here that genetic inactivation of the chromatin-associated SIN3B protein impairs the occurrence of oncogene-induced senescence in vivo and results in a cell-autonomous defect in KRAS-driven production of the proinflammatory IL-1α cytokine.…”

“…We have recently demonstrated that mouse embryonic fibroblasts genetically inactivated for Sin3B are refractory to quiescence as well as oncogene-induced senescence (33)(34)(35). In addition, SIN3B levels are significantly upregulated in preneoplastic senescent lesions in a mouse model of PDAC (34).…”

“…We have recently demonstrated that mouse embryonic fibroblasts genetically inactivated for Sin3B are refractory to quiescence as well as oncogene-induced senescence (33)(34)(35). In addition, SIN3B levels are significantly upregulated in preneoplastic senescent lesions in a mouse model of PDAC (34). Unlike most perturbations that bypass oncogene-induced senescence, Sin3B inactivation is not sufficient to sensitize to oncogenic RAS-induced transformation, providing an experimental context in which these processes are uncoupled (34).…”

“…In addition, SIN3B levels are significantly upregulated in preneoplastic senescent lesions in a mouse model of PDAC (34). Unlike most perturbations that bypass oncogene-induced senescence, Sin3B inactivation is not sufficient to sensitize to oncogenic RAS-induced transformation, providing an experimental context in which these processes are uncoupled (34). Therefore, genetic inactivation of Sin3B represents a unique opportunity to dissect the physiological relevance of cellular senescence in pancreatic cancer progression.…”