FoxO1 Inhibits Sterol Regulatory Element-binding Protein-1c (SREBP-1c) Gene Expression via Transcription Factors Sp1 and SREBP-1c

Deng, Xiong; Zhang, Wenwei; O-Sullivan, InSug; Williams, J. Bradley; Dong, Qi; Park, Edwards A.; Raghow, Rajendra; Unterman, Terry G.; Elam, Marshall B.

doi:10.1074/jbc.m112.347211

Cited by 120 publications

(107 citation statements)

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“…Briefly, SIRT1 affects biological behaviors by targeting SREBP1 and lipogenesis. Activated FoxO1 inhibits SREBP-1c gene expression by reducing transcriptional activity of Sp1 and SREBP-1c and disrupting the assembly of transcriptional initiation complex on the SREBP-1c promoter (34,35). In cancer, SIRT1 suppresses Fox01 activity by deacetylating (36-38), while low expression of Fox01 decreases suppression of SREBP1, consequently resulting in elevated levels of SREBP1.…”

Section: Discussionmentioning

confidence: 99%

SIRT1 promotes endometrial tumor growth by targeting SREBP1 and lipogenesis

Zheng

Qiu

et al. 2014

Oncology Reports

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Abstract. Silent information regulator 1 (SIRT1) is involved in a number of cellular regulatory mechanisms affecting cellular life span, stress resistance, apoptosis and cellular metabolism. Recent studies have revealed that SIRT1 plays a dual role as a tumor suppressor and a tumor promoter in multiple stages of carcinogenesis. Increased lipogenesis has been found in cancer cells, sterol regulatory element binding protein 1 (SREBP1) are nuclear lipogenic transcription factors, which mainly regulate lipogenic processes by activating genes involved in fatty acid and triglyceride biosynthesis. In the present study, we detected expression of SIRT1 in endometrial cancer (EC) and illustrated the relationship between SIRT1 and SREBP1, which indicated that SIRT1 could stimulate endometrial tumor growth through the lipogenic pathway. Gene expression levels of SIRT1 were assayed using quantitative real-time PCR and protein expression levels were detected by western blotting. RNA interference was conducted in order to explore the subsequent effect on tumor cells and on the expression of SREBP1. Expression levels of SIRT1 in EC were found to be significantly higher than in normal endometrium. Knockdown of SIRT1 could downregulate expression of SREBP1 and suppress cell proliferation. These results demonstrated that SIRT1 may play a role as a tumor promoter in EC and can promote endometrial tumor growth by promoting lipogenesis. Our findings suggest that targeting SIRT1 may provide a theoretical basis for the management of EC. IntroductionEndometrial cancer (EC) is the most common malignancy of the female reproductive tract and its incidence is on the increase (1). Approximately 40% of all cases can be attributed to obesity (2). Aberration in lipid metabolism contributes to different aspects of tumorigenesis (3); our research team focused on this domain of EC in recent years.NAD-dependent class III histone deacetylase silent information regulator 1 (SIRT1), that shares the highest degree of homology with the yeast protein SIR2, can deacetylate both histones and non-histone proteins (4). Its deacetylation activity enables it to interact with a variety of important transcription factors and transcriptional co-regulatory factors, to regulate gene transcription, chromosome stability and activity of target proteins, which are involved in tumor metabolism and development (5,6). The current results demonstrated that SIRT1 plays a dual role as a tumor promoter as well as a tumor suppressor (7). Its involvement in tumorigenesis may be due to its diverse distribution in different tissues and different upstream and downstream regulatory factors that regulate its function (8).Sterol regulatory element binding protein 1 (SREBP1) belongs to the family of the basic helix-loop-helix leucine zipper family of DNA binding transcription factors, which can regulate most enzymes involved in fatty acid biosynthesis, such as acetyl-CoA carboxylase, fatty acid synthase, Elovl-6 and stearoyl-CoA desaturase (9). Lipogenesis is increased in cancer cells...

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Section: Discussionmentioning

confidence: 99%

SIRT1 promotes endometrial tumor growth by targeting SREBP1 and lipogenesis

Zheng

Qiu

et al. 2014

Oncology Reports

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“…M0253S). Liver cDNA from transgenic mice expressing a constitutively active Foxo1 was a gift from Dr. Terry G. Unterman (University of Illinois at Chicago College of Medicine) (32). The relative expression of genes of interest was quantified by realtime PCR using the SYBR Green dye-based assay.…”

Section: Methodsmentioning

confidence: 99%

Insulin Is Required to Maintain Albumin Expression by Inhibiting Forkhead Box O1 Protein

Chen

Monks

et al. 2016

Journal of Biological Chemistry

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Diabetes is accompanied by dysregulation of glucose, lipid, and protein metabolism. In recent years, much effort has been spent on understanding how insulin regulates glucose and lipid metabolism, whereas the effect of insulin on protein metabolism has received less attention. In diabetes, hepatic production of serum albumin decreases, and it has been long established that insulin positively controls albumin gene expression. In this study, we used a genetic approach in mice to identify the mechanism by which insulin regulates albumin gene transcription. Albumin expression was decreased significantly in livers with insulin signaling disrupted by ablation of the insulin receptor or Akt. Concomitant deletion of Forkhead Box O1 (Foxo1) in these livers rescued the decreased albumin secretion. Furthermore, activation of Foxo1 in the liver is sufficient to suppress albumin expression. These results suggest that Foxo1 acts as a repressor of albumin expression.

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“…In opposition to their antagonist effects on lipolysis, GCs have been reported to synergize with insulin to potentiate lipogenesis (52)(53)(54)(55). However, FoxO1 has been reported to suppress lipogenic screbp-1c gene expression ( 56 ). Furthermore, FoxO1 can reduce hepatic lipogenic Chrebp protein stability ( 57 ).…”

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confidence: 99%