Repression of endometrial tumor growth by targeting SREBP1 and lipogenesis

Li, Weihua; Tai, Yoshiaki; Zhou, Jie; Gu, Wen; Bai, Zhaofang; Zhou, Tao; Zhong, Zhijiu; McCue, Peter A.; Sang, Nianli; Ji, Jun-Yuan; Kong, Beihua; Jiang, Jie; Wang, Chenguang

doi:10.4161/cc.20811

Cited by 64 publications

(70 citation statements)

References 51 publications

(56 reference statements)

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“…Among the transcriptional activators of lipogenic genes, SREBP-1a is highly expressed in many cancer cell-lines and multiple types of cancer, including endometrial cancer, colorectal cancer and pancreatic cancer (11,26,27). The SREBP-1a level is also correlated with cancer progression and metastasis (28,29).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, SREBP-1a is a potent transcriptional activator for all known SREBP-target genes (7). The SREBP1 protein levels are often correlated with tumor size, histological grade and metastasis, and SREBP1 loss of function inhibits cell proliferation and induces apoptosis, cell migration and invasion in liver, ovarian and endometrial cancers (8)(9)(10)(11). Furthermore, genetic depletion or pharmacological inhibition of SREBP1 has been shown to suppress the epidermal growth factor receptor (EGFR)-induced glioblastoma (12).…”

mentioning

confidence: 99%

“…Interestingly, this small peptide inhibitor could inhibit SREBP-target gene expression in cancer cells. Thus, our data reveals a novel mechanism of PKM2 regulating cancer cell proliferation by stimulating SREBP1-dependent lipid biosynthesis.Among the transcriptional activators of lipogenic genes, SREBP-1a is highly expressed in many cancer cell-lines and multiple types of cancer, including endometrial cancer, colorectal cancer and pancreatic cancer (11,26,27). The SREBP-1a level is also correlated with cancer progression and metastasis (28,29).…”

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confidence: 99%

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Pyruvate kinase M2 interacts with nuclear sterol regulatory element–binding protein 1a and thereby activates lipogenesis and cell proliferation in hepatocellular carcinoma

Zhao

Yang

et al. 2018

Journal of Biological Chemistry

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Dysregulation of lipid metabolism is common in cancer cells, but the underlying mechanisms are poorly understood. Sterol regulatory elementbinding proteins (SREBPs) stimulate lipid biosynthesis through transcriptional activation of lipogenic enzymes. However, SREBPs' roles and potential interacting partners in cancer cells are not fully defined. Using a biochemical approach, we found here that pyruvate kinase M2 (PKM2) physically interacts with the nuclear form of SREBP-1a (nBP1a), by binding to amino acids 43-56 in nBP1a. We also found that PKM2 activates SREBP target gene expression and lipid biosynthesis by stabilizing nBP1a proteins. Using a competitive peptide inhibitor to block the formation of the SREBP-1a/PKM2 complex, we observed that this blockade inhibited lipogenic gene expression. Of note, nBP1a phosphorylation at Thr-59 enhanced the binding to PKM2 and promoted cancer cell growth. Moreover, we show that PKM2 phosphorylates Thr-59 in vitro. Lastly, in human patients with hepatocellular carcinoma, nBP1a phosphorylation at Thr-59 was negatively correlated with clinical outcomes. Together, our results reveal that nBP1a/PKM2 interaction activates lipid metabolism genes in cancer cells and that Thr-59 phosphorylation of SREBP-1a plays an important role in cancer cell proliferation.Lipids are essential for cell proliferation. In fact, it has been estimated that more than 90% fatty acids in tumors cells are derived from de novo biosynthesis, while normal cells obtain lipids primarily from the circulation (1). In several types of cancer, including breast and prostate cancer, fatty acid synthase (Fasn) gene is up regulated (2), suggesting that fatty acid biosynthesis may play a role in cancer pathogenesis. Sterol regulatory element-binding proteins (SREBPs) are conserved transcription factors that can activate the transcription of genes encoding the key lipogenic enzymes, including Fasn (3,4). In mammalian cells, there are three SREBP isoforms (SREBP-1a, -1c and -2) encoded by two different genes, Srebf1 and Srebf2 (5). Two distinct promoters generate SREBP1a and SREBP-1c isoforms from the Srebf1 gene (5). Interestingly, Srebf1a is expressed at higher levels in cancer cells as compared to normal tissues, while Srebf1c is the predominant product of Srebf1 in normal tissues (6). In addition, SREBP-1a is a potent transcriptional activator for all known SREBP-target genes (7). The SREBP1 protein levels are often correlated with tumor size, histological grade and metastasis, and SREBP1 loss of function inhibits cell proliferation and induces apoptosis, cell migration and invasion in liver, ovarian and endometrial cancers (8)(9)(10)(11). Furthermore, genetic depletion or pharmacological inhibition of SREBP1 has been shown to suppress the epidermal growth factor receptor (EGFR)-induced glioblastoma (12). Blocking SREBP pathway prevents hepatocellular carcinoma (HCC) in mouse models (13). Thus, SREBP1 is required to support proliferation in some cancer cells.Previous studies have shown that pyruvate kinase isoform M...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Pyruvate kinase M2 interacts with nuclear sterol regulatory element–binding protein 1a and thereby activates lipogenesis and cell proliferation in hepatocellular carcinoma

Zhao

Yang

et al. 2018

Journal of Biological Chemistry

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“…Accordingly, we established that SIRT1 positively regulates SREBP1 in EC. Our previous study showed that overexpression of SREBP1 was found in EC and it promoted tumor cell proliferation and tumor growth (16), and since the inhibition of SIRT1 can lower the expression of SREBP1, it can suppress tumor growth and progression. We further studied the role of SIRT1 in tumor growth in the following experiment.…”

Section: Effect On Srebp1 With the Silencing Of Sirt1 In Rl95-2 Cell mentioning

confidence: 99%

“…In our previous studies, we demonstrated that SREBP1 is overexpressed in endometrial and ovarian cancer and the expression of SREBP1 protein increased with higher FIGO surgical stage and histological grade of the disease. Furthermore, knockdown of SREBP1 could induce apoptosis, reduce cell proliferation in vitro and in vivo (16,17 …”

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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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ErbB2 Activation Upregulates Glutaminase 1 Expression Which Promotes Breast Cancer Cell Proliferation

Qie

Chu

et al. 2014

J of Cellular Biochemistry

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Active glutamine utilization is critical for tumor cell proliferation. Glutaminolysis represents the first and rate-limiting step of glutamine utilization and is catalyzed by glutaminase (GLS). Activation of ErbB2 is one of the major causes of breast cancers, the second most common cause of death for women in many countries. However, it remains unclear whether ErbB2 signaling affects glutaminase expression in breast cancer cells. In this study, we show that MCF10A-NeuT cell line has higher GLS1 expression at both mRNA and protein levels than its parental line MCF10A, and knockdown of ErbB2 decreases GLS1 expression in MCF10A-NeuT cells. We further show that in these cells, ErbB2-mediated upregulation of GLS1 is not correlated to c-Myc expression. Moreover, activation of neither PI3K-Akt nor MAPK pathway is sufficient to upregulate GLS1 expression. Interestingly, inhibition of NF-κB blocks ErbB2-stimulated GLS1 expression, whereas stimulation of NF-κB is sufficient to enhance GLS1 levels in MCF10A cells, suggesting a PI3K-Akt-independent activation of NF-κB upregulates GLS1 in ErbB2-positive breast cancer cells. Finally, knockdown or inhibition of GLS1 significantly decreased the proliferation of breast cancer cells with high GLS1 levels. Taken together, our data indicate that ErbB2 activation promotes GLS1 expression via a PI3K-Akt-independent NF-κB pathway in breast cancer cells, identifying another oncogenic signaling pathway which stimulates GLS1 expression, and thus promoting glutamine utilization in cancer cells. These findings, if validated by in vivo model, may facilitate the identification of novel biochemical targets for cancer prevention and therapy.

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Repression of endometrial tumor growth by targeting SREBP1 and lipogenesis

Cited by 64 publications

References 51 publications

Pyruvate kinase M2 interacts with nuclear sterol regulatory element–binding protein 1a and thereby activates lipogenesis and cell proliferation in hepatocellular carcinoma

Pyruvate kinase M2 interacts with nuclear sterol regulatory element–binding protein 1a and thereby activates lipogenesis and cell proliferation in hepatocellular carcinoma

SIRT1 promotes endometrial tumor growth by targeting SREBP1 and lipogenesis

ErbB2 Activation Upregulates Glutaminase 1 Expression Which Promotes Breast Cancer Cell Proliferation

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