The Molecular Mechanism Of SIRT1 Transcription Induced By Stress Response And Involment In Human Disease

The word "Stress" was originally derived from physics and meant "tension or pressure". In 1936, Canadian physiologist Serry recoined the term to describe a specific pathophysiological process, linking extrinsic stimulations (stressors) to intrinsic reponses. Through his observation of the patients and abundant animal’s experimenttal, Serry formulated the theory of stress. What Serry described at that time mostly concerned with physiological stress, but it is now generally believed that stress underscores the pathogenesis of human diseases.Stress (Stress Response) refers to all the non-specific responses the body presented caused as a result of the deleterious stimulations. The responses sometimes are restricted, such as hypoxia stress and inflammation; they also can be systemic, such as metabolic syndrome. However, it is usually the uniform reaction of the body regardless of the type of localized or systemic response. The stress reponse is widely existed in human diseases, which provides the rationale for continuing the research in this field.Hypoxia is an important stressor for the promotion of cancer cell migration and invasion, modulating a series of molecular events involved in tmor progression. SIRT1 belongs to the mammalian sirtuin family, controls the expression and/or activity of several tumor-associated factors and plays an important role in tumorrigenesis. To date, the precise role SIRT1 plays in hypoxia-induced tumor progression is obscure. Here" we report that SIRT1, a multifaceted player in tumorigenesis, opposed ovarian cancer metastasis in vitro and in vivo by impeding EMT. Hypoxic stress downregulated the expression of SIRT1, primarily at the transcriptional level, by reducing the occupancy of the transcriptional activator Spl and increasing the occupancy of the transcriptional repressor HIC1 on the proximal promoter of the SIRT1 gene in a SUMOylation-dependent manner. Further analysis revealed that the SUMO E3 ligase PIASy (also known as PIAS4) was induced by hypoxia and prevented Spl from binding to the SIRT1 promoter. Conversely, knockdown of PIASy by small interfering RNA (siRNA) restored Spl binding and SIRT1 expression in cancer cells challenged with hypobaric hypoxia, reversed cancer cell EMT, and attenuated metastasis in vivo in nude mice. Importantly, analysis of human ovarian tumor specimens indicated that PIASy expression was positively, whereas SIRT1 expression was inversely, correlated with cancer aggressiveness. In summary, our work has identified a new pathway that links downregulation of SIRT1 to hypoxia-induced EMT in ovarian cancer cells and, as such, sheds light on the development of novel anti-tumor therapeutics.Compared to the control mice, NASH mice exhibit increased expression and binding activity of PIAS4, a SUMO E3 ligase that has been shown to repress SIRT1 expression, in the liver. Exposure to high glucose stimulated the expression and activity of PIAS4 in cultured hepatocyte (HepG2). PIAS4 over-expression in HepG2 cells enhanced NF-B activity. In contrast, depletion of PIAS4 restored SIRT1 expression in HepG2 cells and dampened the synthesis of pro-inflammatory mediators. Importantly, PIAS4 knockdown alleviated hepatic pathologies, normalized SIRT1 expression, and ameliorated hepatic inflammation in NASH mice. PIAS4 silencing in vitro and in vivo was accompanied by the normalization of NF-B activity. PIAS4 mediated SIRT1 repression in response to nutrient surplus contributes to the pathogenesis of NASH through impacting the SIRT1-NF- B interplay. Therefore, targeting PIAS4 might provide novel therapeutic strategies in the intervention of NASH.SIRT1 has been implicated in the regulation of diabetes, by improving insulin resistance and protecting pancreatic β cells. Chaetocin was first discovered as an inhibitor of H3K9 methyltransferase used in cancer treatment. Our unpublished data have found that chaetocin can protect the heart from myocardial infarction caused by myocardial ischemia, and epigenetic regulation on SIRT1 transcription activity. We found that chaetocin improved the insulin sensitivity both in diet-induced type 2 diabetes model and a genetically predisposed type 2 diabetes model. Therefore, chaetocin might offer a novel therapeutic strategies in the intervention of type 2 diabetes.In summary, this thesis focuses on the mechanism involved in stress-induced SIRT1 transcription, and the pathogenesis of ovarian cancer metastasis, NASH and type 2 diabetes. The key findings outlined in this report provide a new potential target and clue for the treatment of SIRT1-related disease.