PROX1-mediated Epigenetic Silencing of Contributes to Proliferation and Glucose Metabolism in Colorectal Cancer

Overview

Journal Int J Biol Sci

Specialty Biology

Date 2023 Jan 3

PMID 36594098

Authors

Lu Gan

Qingguo Li

Wei Nie

Yi Zhang

Hesheng Jiang

Cong Tan

Long Zhang

Jieyun Zhang

Qian Li

Pengcong Hou

Yitao Yuan

Xun Sun

Dongmei Liu

Weiqi Sheng

Tianshu Liu

Midie Xu

Weijian Guo

Affiliations

Soon will be listed here.

Abstract

Prospero-related homeobox 1 (PROX1) is a homeobox transcription factor known to promote malignant transformation and stemness in human colorectal cancer (CRC). However, the biological function of PROX1 in metabolic rearrangement in CRC remains unclear. Here, we aimed to uncover the relationship between the expression profile and role of PROX1 and CRC cell glucose metabolism and to elucidate the underlying molecular mechanism. PROX1 expression was significantly upregulated in human CRC tissues and positively associated with the maximum standardized uptake value (SUVmax), a measure of tissue 18-fluoro-2-deoxy-D-glucose uptake and an indicator of glycolysis and tumor cell activity, in patients with CRC. Knockdown of PROX1 suppressed CRC cell proliferation and glucose metabolism and . Mechanistically, through a physical interaction, PROX1 recruited EZH2 to the SIRT3 promoter and inhibited promoter activity. Moreover, PROX1 or EZH2 knockdown decreased cell glycolysis by targeting . Clinically, high PROX1 expression combined with low expression predicted poor prognosis in patients with CRC. Thus, our study suggests that the PROX1-EZH2 complex positively regulates cell proliferation and glucose metabolism by engaging in CRC, which may serve as a promising therapeutic strategy for CRC.

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References

Srinivasan R, Escobedo N, Yang Y, Interiano A, Dillard M, Finkelstein D . The Prox1-Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors. Genes Dev. 2014; 28(19):2175-87. PMC: 4180978. DOI: 10.1101/gad.216226.113. View

Liu Y, Ye X, Zhang J, Ouyang H, Shen Z, Wu Y . PROX1 promotes hepatocellular carcinoma proliferation and sorafenib resistance by enhancing β-catenin expression and nuclear translocation. Oncogene. 2015; 34(44):5524-35. DOI: 10.1038/onc.2015.7. View

Huang M, Yang Y, Li Q, Wang C, Liang L, Zhu X . Induction Chemotherapy Followed by Primary Tumor Resection Did Not Bring Survival Benefits in Colon Cancer Patients With Asymptomatic Primary Lesion and Synchronous Unresectable Metastases. Front Oncol. 2022; 12:747124. PMC: 8841852. DOI: 10.3389/fonc.2022.747124. View

Margueron R, Reinberg D . The Polycomb complex PRC2 and its mark in life. Nature. 2011; 469(7330):343-9. PMC: 3760771. DOI: 10.1038/nature09784. View

Nie W, Xu M, Gan L, Huang H, Xiu Q, Li B . Overexpression of stathmin 1 is a poor prognostic biomarker in non-small cell lung cancer. Lab Invest. 2014; 95(1):56-64. DOI: 10.1038/labinvest.2014.124. View

Vilorio-Marques L, Martin V, Diez-Tascon C, Gonzalez-Sevilla M, Fernandez-Villa T, Honrado E . The role of EZH2 in overall survival of colorectal cancer: a meta-analysis. Sci Rep. 2017; 7(1):13806. PMC: 5653815. DOI: 10.1038/s41598-017-13670-z. View

Ouyang H, Qin Y, Liu Y, Xie Y, Liu J . Prox1 directly interacts with LSD1 and recruits the LSD1/NuRD complex to epigenetically co-repress CYP7A1 transcription. PLoS One. 2013; 8(4):e62192. PMC: 3633876. DOI: 10.1371/journal.pone.0062192. View

Wei F, Cao Z, Wang X, Wang H, Cai M, Li T . Epigenetic regulation of autophagy by the methyltransferase EZH2 through an MTOR-dependent pathway. Autophagy. 2016; 11(12):2309-22. PMC: 4835210. DOI: 10.1080/15548627.2015.1117734. View

Torrens-Mas M, Hernandez-Lopez R, Pons D, Roca P, Oliver J, Sastre-Serra J . Sirtuin 3 silencing impairs mitochondrial biogenesis and metabolism in colon cancer cells. Am J Physiol Cell Physiol. 2019; 317(2):C398-C404. DOI: 10.1152/ajpcell.00112.2019. View

10.

Khodaei F, Hosseini S, Omidi M, Hosseini S, Rezaei M . Cytotoxicity of metformin against HT29 colon cancer cells contributes to mitochondrial Sirt3 upregulation. J Biochem Mol Toxicol. 2020; 35(3):e22662. DOI: 10.1002/jbt.22662. View

11.

Torrens-Mas M, Oliver J, Roca P, Sastre-Serra J . SIRT3: Oncogene and Tumor Suppressor in Cancer. Cancers (Basel). 2017; 9(7). PMC: 5532626. DOI: 10.3390/cancers9070090. View

12.

Shimoda M, Takahashi M, Yoshimoto T, Kono T, Ikai I, Kubo H . A homeobox protein, prox1, is involved in the differentiation, proliferation, and prognosis in hepatocellular carcinoma. Clin Cancer Res. 2006; 12(20 Pt 1):6005-11. DOI: 10.1158/1078-0432.CCR-06-0712. View

13.

Laerm A, Helmbold P, Goldberg M, Dammann R, Holzhausen H, Ballhausen W . Prospero-related homeobox 1 (PROX1) is frequently inactivated by genomic deletions and epigenetic silencing in carcinomas of the bilary system. J Hepatol. 2006; 46(1):89-97. DOI: 10.1016/j.jhep.2006.07.033. View

14.

Chen F, Chen J, Yang L, Liu J, Zhang X, Zhang Y . Extracellular vesicle-packaged HIF-1α-stabilizing lncRNA from tumour-associated macrophages regulates aerobic glycolysis of breast cancer cells. Nat Cell Biol. 2019; 21(4):498-510. DOI: 10.1038/s41556-019-0299-0. View

15.

Zhang X, Duan R, Wang Y, Liu X, Zhang W, Zhu X . FOLFIRI (folinic acid, fluorouracil, and irinotecan) increases not efficacy but toxicity compared with single-agent irinotecan as a second-line treatment in metastatic colorectal cancer patients: a randomized clinical trial. Ther Adv Med Oncol. 2022; 14:17588359211068737. PMC: 8771434. DOI: 10.1177/17588359211068737. View

16.

Ansari A, Rahman M, Saha S, Saikot F, Deep A, Kim K . Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease. Aging Cell. 2016; 16(1):4-16. PMC: 5242307. DOI: 10.1111/acel.12538. View

17.

Bremer S, Conradi L, Mechie N, Amanzada A, Mavropoulou E, Kitz J . Enhancer of Zeste Homolog 2 in Colorectal Cancer Development and Progression. Digestion. 2019; 102(2):227-235. DOI: 10.1159/000504093. View

18.

Liu C, Huang Z, Jiang H, Shi F . The sirtuin 3 expression profile is associated with pathological and clinical outcomes in colon cancer patients. Biomed Res Int. 2014; 2014:871263. PMC: 4101237. DOI: 10.1155/2014/871263. View

19.

Torrens-Mas M, Hernandez-Lopez R, Oliver J, Roca P, Sastre-Serra J . Sirtuin 3 silencing improves oxaliplatin efficacy through acetylation of MnSOD in colon cancer. J Cell Physiol. 2018; 233(8):6067-6076. DOI: 10.1002/jcp.26443. View

20.

Li Q, Zhang D, Chen X, He L, Li T, Xu X . Nuclear PKM2 contributes to gefitinib resistance via upregulation of STAT3 activation in colorectal cancer. Sci Rep. 2015; 5:16082. PMC: 4635355. DOI: 10.1038/srep16082. View