Carbohydrate Response Element Binding Protein (ChREBP) Correlates with Colon Cancer Progression and Contributes to Cell Proliferation

Overview

Journal Sci Rep

Specialty Science

Date 2020 Mar 8

PMID 32144313

Citations 11

Authors

Yu Lei

Shuling Zhou

Qiaoling Hu

Xueling Chen

Jiang Gu

Affiliations

Soon will be listed here.

Abstract

Cancers are characterized by reprogrammed glucose metabolisms to fuel cell growth and proliferation. Carbohydrate response element binding protein (ChREBP) is a glucose-mediated transcription factor that strongly regulates glycolytic and lipogenic pathways. It has been shown to associate with metabolic diseases, such as obesity, diabetes and non-alcoholic fatty liver diseases. However, how it associates with cancers has not been well understood. In this study, ChREBP expression was assessed by immunohistochemistry in colon tissue arrays containing normal colon tissue and cancer tissue at different clinical stages. Tissue mRNA levels of ChREBP were also measured in a cohort of colon cancer patients. We found that ChREBP mRNA and protein expression were significantly increased in colon cancer tissue compared to healthy colon (p < 0.001), and their expression was positively correlated to colon malignancy (for mRNA, p = 0.002; for protein p < 0.001). Expression of lipogenic genes (ELOVL6 and SCD1) in colon cancer was also positively associated with colon malignancy (for both genes, p < 0.001). In vitro, ChREBP knockdown with siRNA transfection inhibited cell proliferation and induced cell cycle arrest without changes in apoptosis in colon cancer cell lines (HT29, DLD1 and SW480). Glycolytic and lipogenic pathways were inhibited but the p53 pathway was activated after ChREBP knockdown. Taken together, ChREBP expression is associated with colon malignancy and it might contribute to cell proliferation via promoting anabolic pathways and inhibiting p53. In addition, ChREBP might represent a novel clinical useful biomarker to evaluate the malignancy of colon cancer.

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References

Iizuka K, Bruick R, Liang G, Horton J, Uyeda K . Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc Natl Acad Sci U S A. 2004; 101(19):7281-6. PMC: 409910. DOI: 10.1073/pnas.0401516101. View

Yamashita H, Takenoshita M, Sakurai M, Bruick R, Henzel W, Shillinglaw W . A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver. Proc Natl Acad Sci U S A. 2001; 98(16):9116-21. PMC: 55382. DOI: 10.1073/pnas.161284298. View

Cairo S, Merla G, Urbinati F, Ballabio A, Reymond A . WBSCR14, a gene mapping to the Williams--Beuren syndrome deleted region, is a new member of the Mlx transcription factor network. Hum Mol Genet. 2001; 10(6):617-27. DOI: 10.1093/hmg/10.6.617. View

Ishii S, Iizuka K, Miller B, Uyeda K . Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription. Proc Natl Acad Sci U S A. 2004; 101(44):15597-602. PMC: 524841. DOI: 10.1073/pnas.0405238101. View

Bricambert J, Miranda J, Benhamed F, Girard J, Postic C, Dentin R . Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice. J Clin Invest. 2010; 120(12):4316-31. PMC: 2993582. DOI: 10.1172/JCI41624. View

Guinez C, Filhoulaud G, Rayah-Benhamed F, Marmier S, Dubuquoy C, Dentin R . O-GlcNAcylation increases ChREBP protein content and transcriptional activity in the liver. Diabetes. 2011; 60(5):1399-413. PMC: 3292313. DOI: 10.2337/db10-0452. View

Passam H, Berden J, SLATER E . The cytochrome b spectrum of plant mitochondria and its response to ATP and antimycin. Biochim Biophys Acta. 1973; 325(1):54-61. DOI: 10.1016/0005-2728(73)90150-3. View

Marche M, Basurko M, Cassaigne A . Interaction of phosphonates related to glutathione with the rat kidney gamma-glutamylcysteine synthetase. Biochimie. 1987; 69(5):461-7. DOI: 10.1016/0300-9084(87)90083-6. View

Bianchini F, Kaaks R, Vainio H . Overweight, obesity, and cancer risk. Lancet Oncol. 2002; 3(9):565-74. DOI: 10.1016/s1470-2045(02)00849-5. View

10.

Kim J, Dang C . Cancer's molecular sweet tooth and the Warburg effect. Cancer Res. 2006; 66(18):8927-30. DOI: 10.1158/0008-5472.CAN-06-1501. View

11.

Tong X, Zhao F, Thompson C . The molecular determinants of de novo nucleotide biosynthesis in cancer cells. Curr Opin Genet Dev. 2009; 19(1):32-7. PMC: 2707261. DOI: 10.1016/j.gde.2009.01.002. View

12.

Hatzivassiliou G, Zhao F, Bauer D, Andreadis C, Shaw A, Dhanak D . ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell. 2005; 8(4):311-21. DOI: 10.1016/j.ccr.2005.09.008. View

13.

Airley R, McHugh P, Evans A, Harris B, Winchester L, Buffa F . Role of carbohydrate response element-binding protein (ChREBP) in generating an aerobic metabolic phenotype and in breast cancer progression. Br J Cancer. 2013; 110(3):715-23. PMC: 3915128. DOI: 10.1038/bjc.2013.765. View

14.

Calvisi D, Wang C, Ho C, Ladu S, Lee S, Mattu S . Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology. 2010; 140(3):1071-83. PMC: 3057329. DOI: 10.1053/j.gastro.2010.12.006. View

15.

You Y, Chen J, Zhu F, Xu Q, Han L, Gao X . Glutaredoxin 1 up-regulates deglutathionylation of α4 integrin and thereby restricts neutrophil mobilization from bone marrow. J Biol Chem. 2019; 294(8):2616-2627. PMC: 6393595. DOI: 10.1074/jbc.RA118.006096. View

16.

Tong X, Zhao F, Mancuso A, Gruber J, Thompson C . The glucose-responsive transcription factor ChREBP contributes to glucose-dependent anabolic synthesis and cell proliferation. Proc Natl Acad Sci U S A. 2009; 106(51):21660-5. PMC: 2799883. DOI: 10.1073/pnas.0911316106. View

17.

Metukuri M, Zhang P, Basantani M, Chin C, Stamateris R, Alonso L . ChREBP mediates glucose-stimulated pancreatic β-cell proliferation. Diabetes. 2012; 61(8):2004-15. PMC: 3402328. DOI: 10.2337/db11-0802. View

18.

Yu Y, Maguire T, Alwine J . ChREBP, a glucose-responsive transcriptional factor, enhances glucose metabolism to support biosynthesis in human cytomegalovirus-infected cells. Proc Natl Acad Sci U S A. 2014; 111(5):1951-6. PMC: 3918764. DOI: 10.1073/pnas.1310779111. View

19.

Poungvarin N, Lee J, Yechoor V, Li M, Assavapokee T, Suksaranjit P . Carbohydrate response element-binding protein (ChREBP) plays a pivotal role in beta cell glucotoxicity. Diabetologia. 2012; 55(6):1783-96. PMC: 4010252. DOI: 10.1007/s00125-012-2506-4. View

20.

Zhang P, Kumar A, Katz L, Li L, Paulynice M, Herman M . Induction of the ChREBPβ Isoform Is Essential for Glucose-Stimulated β-Cell Proliferation. Diabetes. 2015; 64(12):4158-70. PMC: 4657577. DOI: 10.2337/db15-0239. View