CD36 Inhibits β-catenin/c-myc-mediated Glycolysis Through Ubiquitination of GPC4 to Repress Colorectal Tumorigenesis

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Sep 6

PMID 31484922

Citations 101

Authors

Yuan Fang

Zhi-Yong Shen

Yi-Zhi Zhan

Xiao-Chuang Feng

Ke-Li Chen

Yong-Sheng Li

Hai-Jun Deng

Su-Ming Pan

De-Hua Wu

Yi Ding

Affiliations

Soon will be listed here.

Abstract

The diverse expression pattern of CD36 reflects its multiple cellular functions. However, the roles of CD36 in colorectal cancer (CRC) remain unknown. Here, we discover that CD36 expression is progressively decreased from adenomas to carcinomas. CD36 loss predicts poor survival of CRC patients. In CRC cells, CD36 acts as a tumor suppressor and inhibits aerobic glycolysis in vitro and in vivo. Mechanically, CD36-Glypcian 4 (GPC4) interaction could promote the proteasome-dependent ubiquitination of GPC4, followed by inhibition of β-catenin/c-myc signaling and suppression of downstream glycolytic target genes GLUT1, HK2, PKM2 and LDHA. Moreover, disruption of CD36 in inflammation-induced CRC model as well as Apc mice model significantly increased colorectal tumorigenesis. Our results reveal a CD36-GPC4-β-catenin-c-myc signaling axis that regulates glycolysis in CRC development and may provide an intervention strategy for CRC prevention.

Citing Articles

PGK1 enhances productive bovine herpesvirus 1 infection by stimulating β-catenin-dependent transcription.

Li X, Gu W, Li S, Fiorito F, Ding X, Zhu L Vet Res. 2025; 56(1):50.

PMID: 40055833 PMC: 11887390. DOI: 10.1186/s13567-025-01480-5.

Sirt6 loss activates Got1 and facilitates cleft palate through abnormal activating glycolysis.

Wang X, Zhao X, Zheng X, Peng X, Chen J, Wang Y Cell Death Dis. 2025; 16(1):159.

PMID: 40050262 PMC: 11885815. DOI: 10.1038/s41419-025-07465-8.

Dual activation of GCGR/GLP1R signaling ameliorates intestinal fibrosis metabolic regulation of histone H3K9 lactylation in epithelial cells.

Liu H, Hong Y, Chen H, Wang X, Dong J, Li X Acta Pharm Sin B. 2025; 15(1):278-295.

PMID: 40041889 PMC: 11873616. DOI: 10.1016/j.apsb.2024.11.017.

HACD2 Promotes Pancreatic Cancer Progression by Enhancing PKM2 Dissociation From PRKN in a Dehydratase-Independent Manner.

Chu X, Zhao J, Shen Y, Feng Q, Zhou C, Ma L Adv Sci (Weinh). 2025; 12(10):e2407942.

PMID: 39836601 PMC: 11904967. DOI: 10.1002/advs.202407942.

CD36 enrichment in HER2-positive mesenchymal stem cells drives therapy refractoriness in breast cancer.

Castagnoli L, Franceschini A, Cancila V, Dugo M, Bigliardi M, Chiodoni C J Exp Clin Cancer Res. 2025; 44(1):19.

PMID: 39833955 PMC: 11744895. DOI: 10.1186/s13046-025-03276-z.

References

Zhou L, Wang Y, Zhou M, Zhang Y, Wang P, Li X . HOXA9 inhibits HIF-1α-mediated glycolysis through interacting with CRIP2 to repress cutaneous squamous cell carcinoma development. Nat Commun. 2018; 9(1):1480. PMC: 5902613. DOI: 10.1038/s41467-018-03914-5. View

Pavlova N, Thompson C . The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016; 23(1):27-47. PMC: 4715268. DOI: 10.1016/j.cmet.2015.12.006. View

Uray I, Liang Y, Hyder S . Estradiol down-regulates CD36 expression in human breast cancer cells. Cancer Lett. 2004; 207(1):101-7. DOI: 10.1016/j.canlet.2003.10.021. View

Coburn C, Knapp Jr F, Febbraio M, Beets A, Silverstein R, Abumrad N . Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J Biol Chem. 2000; 275(42):32523-9. DOI: 10.1074/jbc.M003826200. View

Pate K, Stringari C, Sprowl-Tanio S, Wang K, TeSlaa T, Hoverter N . Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer. EMBO J. 2014; 33(13):1454-73. PMC: 4194089. DOI: 10.15252/embj.201488598. View

Peck B, Schulze A . Lipid desaturation - the next step in targeting lipogenesis in cancer?. FEBS J. 2016; 283(15):2767-78. DOI: 10.1111/febs.13681. View

Fico A, Maina F, Dono R . Fine-tuning of cell signaling by glypicans. Cell Mol Life Sci. 2007; 68(6):923-9. PMC: 11114805. DOI: 10.1007/s00018-007-7471-6. View

Kim J, Woo A, Chu J, Snow J, Fujiwara Y, Kim C . A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell. 2010; 143(2):313-24. PMC: 3018841. DOI: 10.1016/j.cell.2010.09.010. View

Fico A, de Chevigny A, Egea J, Bosl M, Cremer H, Maina F . Modulating Glypican4 suppresses tumorigenicity of embryonic stem cells while preserving self-renewal and pluripotency. Stem Cells. 2012; 30(9):1863-74. DOI: 10.1002/stem.1165. View

10.

Cao J, Ma J, Sun L, Li J, Qin T, Zhou C . Targeting glypican-4 overcomes 5-FU resistance and attenuates stem cell-like properties via suppression of Wnt/β-catenin pathway in pancreatic cancer cells. J Cell Biochem. 2018; 119(11):9498-9512. DOI: 10.1002/jcb.27266. View

11.

Pan J, Fan Z, Wang Z, Dai Q, Xiang Z, Yuan F . CD36 mediates palmitate acid-induced metastasis of gastric cancer via AKT/GSK-3β/β-catenin pathway. J Exp Clin Cancer Res. 2019; 38(1):52. PMC: 6360779. DOI: 10.1186/s13046-019-1049-7. View

12.

Jiao L, Zhang H, Li D, Yang K, Tang J, Li X . Regulation of glycolytic metabolism by autophagy in liver cancer involves selective autophagic degradation of HK2 (hexokinase 2). Autophagy. 2017; 14(4):671-684. PMC: 5959330. DOI: 10.1080/15548627.2017.1381804. View

13.

Kaur B, Cork S, Sandberg E, Devi N, Zhang Z, Klenotic P . Vasculostatin inhibits intracranial glioma growth and negatively regulates in vivo angiogenesis through a CD36-dependent mechanism. Cancer Res. 2009; 69(3):1212-20. PMC: 2659670. DOI: 10.1158/0008-5472.CAN-08-1166. View

14.

Sung J . Is aspirin for colorectal cancer prevention on the prime time yet?. Gut. 2014; 63(11):1691-2. DOI: 10.1136/gutjnl-2014-306780. View

15.

Mosimann C, Hausmann G, Basler K . Beta-catenin hits chromatin: regulation of Wnt target gene activation. Nat Rev Mol Cell Biol. 2009; 10(4):276-86. DOI: 10.1038/nrm2654. View

16.

Zheng Y, Li L, Jia Y, Zhang B, Li J, Zhu Y . LINC01554-Mediated Glucose Metabolism Reprogramming Suppresses Tumorigenicity in Hepatocellular Carcinoma via Downregulating PKM2 Expression and Inhibiting Akt/mTOR Signaling Pathway. Theranostics. 2019; 9(3):796-810. PMC: 6376468. DOI: 10.7150/thno.28992. View

17.

Rege T, Stewart Jr J, Dranka B, Benveniste E, Silverstein R, Gladson C . Thrombospondin-1-induced apoptosis of brain microvascular endothelial cells can be mediated by TNF-R1. J Cell Physiol. 2008; 218(1):94-103. PMC: 2597846. DOI: 10.1002/jcp.21570. View

18.

Watt M, Clark A, Selth L, Haynes V, Lister N, Rebello R . Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer. Sci Transl Med. 2019; 11(478). DOI: 10.1126/scitranslmed.aau5758. View

19.

Tsuchida T, Kijima H, Tokunaga T, Oshika Y, Hatanaka H, Fukushima Y . Expression of the thrombospondin 1 receptor CD36 is correlated with decreased stromal vascularisation in colon cancer. Int J Oncol. 1998; 14(1):47-51. View

20.

Osthus R, Shim H, Kim S, Li Q, Reddy R, Mukherjee M . Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem. 2000; 275(29):21797-800. DOI: 10.1074/jbc.C000023200. View