E2F Transcription Factor 1 (E2F1) Promotes the Transforming Growth Factor TGF-β1 Induced Human Cardiac Fibroblasts Differentiation Through Promoting the Transcription of CCNE2 Gene

Overview

Journal Bioengineered

Date 2021 Sep 15

PMID 34521301

Citations 4

Authors

Rongheng Liao

Bo Xie

Jun Cui

Zhen Qi

Song Xue

Yongyi Wang

Affiliations

Soon will be listed here.

Abstract

The differentiation of cardiac fibroblast to myofibroblast is the key process of cardiac fibrosis. In the study, we aimed to determine the function of E2F Transcription Factor 1 (E2F1) in human cardiac fibroblasts (HCFs) differentiation, search for its downstream genes and elucidate the function of them in HCFs differentiation. As a result, we found that E2F1 was up-regulated in TGF-β1-induced HCFs differentiation. Silencing the expression of E2F1 by siRNA in HCFs, we found that the expression of differentiation-related genes (Collagen-1, α-Smooth muscle actin, and Fibronectin-1) was significantly suppressed, combining with proliferation and migration assay, we determined that HCFs differentiation was decreased. Luciferase report assay and immunoprecipitation proved that the oncogene CCNE2 was a direct target gene of E2F1, overexpression of CCNE2 was found in differentiated HCFs, silencing the expression of CCNE2 by siRNA decreased HCFs differentiation. Our research suggested that E2F1 and its downstream target gene CCNE2 play a vital role in TGF-β1-induced HCFs differentiation, thus E2F1 and CCNE2 may be a potential therapeutic target for cardiac fibrosis.

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References

Wang J, Xu N, Feng X, Hou N, Zhang J, Cheng X . Targeted disruption of Smad4 in cardiomyocytes results in cardiac hypertrophy and heart failure. Circ Res. 2005; 97(8):821-8. DOI: 10.1161/01.RES.0000185833.42544.06. View

Gao F, Kataoka M, Liu N, Liang T, Huang Z, Gu F . Therapeutic role of miR-19a/19b in cardiac regeneration and protection from myocardial infarction. Nat Commun. 2019; 10(1):1802. PMC: 6470165. DOI: 10.1038/s41467-019-09530-1. View

Travers J, Kamal F, Robbins J, Yutzey K, Blaxall B . Cardiac Fibrosis: The Fibroblast Awakens. Circ Res. 2016; 118(6):1021-40. PMC: 4800485. DOI: 10.1161/CIRCRESAHA.115.306565. View

Weber K . Fibrosis and hypertensive heart disease. Curr Opin Cardiol. 2001; 15(4):264-72. DOI: 10.1097/00001573-200007000-00010. View

Dapas B, Farra R, Grassi M, Giansante C, Fiotti N, Uxa L . Role of E2F1-cyclin E1-cyclin E2 circuit in human coronary smooth muscle cell proliferation and therapeutic potential of its downregulation by siRNAs. Mol Med. 2009; 15(9-10):297-306. PMC: 2710289. DOI: 10.2119/molmed.2009.00030. View

Riverso M, Montagnani V, Stecca B . KLF4 is regulated by RAS/RAF/MEK/ERK signaling through E2F1 and promotes melanoma cell growth. Oncogene. 2017; 36(23):3322-3333. PMC: 5474568. DOI: 10.1038/onc.2016.481. View

Khalil H, Kanisicak O, Prasad V, Correll R, Fu X, Schips T . Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest. 2017; 127(10):3770-3783. PMC: 5617658. DOI: 10.1172/JCI94753. View

Kanehisa M, Goto S . KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 1999; 28(1):27-30. PMC: 102409. DOI: 10.1093/nar/28.1.27. View

Xu Z, Qu H, Ren Y, Gong Z, Ri H, Chen X . An Update on the Potential Roles of E2F Family Members in Colorectal Cancer. Cancer Manag Res. 2021; 13:5509-5521. PMC: 8277564. DOI: 10.2147/CMAR.S320193. View

10.

Lai Q, Giralt A, Le May C, Zhang L, Cariou B, Denechaud P . E2F1 inhibits circulating cholesterol clearance by regulating Pcsk9 expression in the liver. JCI Insight. 2017; 2(10). PMC: 5436545. DOI: 10.1172/jci.insight.89729. View

11.

Cui J, Qi S, Liao R, Su D, Wang Y, Xue S . MiR-574-5p promotes the differentiation of human cardiac fibroblasts via regulating ARID3A. Biochem Biophys Res Commun. 2019; 521(2):427-433. DOI: 10.1016/j.bbrc.2019.09.107. View

12.

Zhang Y, Xu N, Xu J, Kong B, Copple B, Guo G . E2F1 is a novel fibrogenic gene that regulates cholestatic liver fibrosis through the Egr-1/SHP/EID1 network. Hepatology. 2014; 60(3):919-30. PMC: 4146672. DOI: 10.1002/hep.27121. View

13.

Meng X, Nikolic-Paterson D, Lan H . TGF-β: the master regulator of fibrosis. Nat Rev Nephrol. 2016; 12(6):325-38. DOI: 10.1038/nrneph.2016.48. View

14.

Shi J, Li J, Yang S, Hu X, Chen J, Feng J . LncRNA SNHG3 is activated by E2F1 and promotes proliferation and migration of non-small-cell lung cancer cells through activating TGF-β pathway and IL-6/JAK2/STAT3 pathway. J Cell Physiol. 2019; 235(3):2891-2900. DOI: 10.1002/jcp.29194. View

15.

Kong P, Christia P, Frangogiannis N . The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 2013; 71(4):549-74. PMC: 3769482. DOI: 10.1007/s00018-013-1349-6. View

16.

Shull M, Ormsby I, Kier A, Pawlowski S, Diebold R, Yin M . Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992; 359(6397):693-9. PMC: 3889166. DOI: 10.1038/359693a0. View

17.

Jin B, Kim H, Kim E, Chung T, Ha K, An H . 6'-Sialyllactose Ameliorates In Vivo and In Vitro Benign Prostatic Hyperplasia by Regulating the E2F1/pRb-AR Pathway. Nutrients. 2019; 11(9). PMC: 6770807. DOI: 10.3390/nu11092203. View

18.

Schwarz J, Bassing C, Kovesdi I, Datto M, Blazing M, George S . Expression of the E2F1 transcription factor overcomes type beta transforming growth factor-mediated growth suppression. Proc Natl Acad Sci U S A. 1995; 92(2):483-7. PMC: 42765. DOI: 10.1073/pnas.92.2.483. View

19.

Dassanayaka S, Brittian K, Jurkovic A, Higgins L, Audam T, Long B . E2f1 deletion attenuates infarct-induced ventricular remodeling without affecting O-GlcNAcylation. Basic Res Cardiol. 2019; 114(4):28. PMC: 7278029. DOI: 10.1007/s00395-019-0737-y. View

20.

Yang X, Letterio J, Lechleider R, Chen L, Hayman R, Gu H . Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. EMBO J. 1999; 18(5):1280-91. PMC: 1171218. DOI: 10.1093/emboj/18.5.1280. View