E2F Transcription Factor 1 Activates FKBP Prolyl Isomerase 4 to Promote Angiogenesis in Cervical Squamous Cell Carcinoma Via the PI3K/AKT Signaling Pathway

Overview

Journal Reprod Sci

Publisher Springer

Specialty Reproductive Medicine

Date 2022 Jul 18

PMID 35849266

Authors

Jiazhen Huang

Ying Zhao

Affiliations

Soon will be listed here.

Abstract

Angiogenesis, namely the formation of blood vessels, is crucial for tumor growth, metastasis and development. E2F transcription factor 1 (E2F1) has been linked to tumorigenesis in several human cancers. This work examines the role of E2F1 and its downstream targets in angiogenesis in cervical squamous cell carcinoma (CSCC). E2F1 was predicted as a candidate oncogene in CSCC using a GSE63514 dataset. Increased E2F1 expression was detected in CSCC tumor samples and cell lines by RT-qPCR, immunohistochemistry, and western blot assays. E2F1 downregulation reduced the angiogenesis activity of HUVECs and the invasiveness of CSCC cells. In vivo, E2F1 knockdown also reduced the xenograft tumor growth and promoted tumor necrosis in mice. FKBP prolyl isomerase 4 (FKBP4) was identified as a target of E2F1. E2F1 bound to FKBP4 promoter for transcriptional activation. Further upregulation of FKBP4 blocked the tumor-suppressive role of E2F1 silencing. FKBP4 was enriched in the PI3K/AKT signaling. In cells and xenograft tumors, the E2F1/FKBP4 axis promoted PI3K and AKT phosphorylation. Activation of the PI3K/AKT signaling restored the angiogenesis activity in cells blocked by E2F1 silencing. In summary, this work demonstrates that E2F1 promotes FKBP4 transcription to activate the PI3K/AKT pathway, which augments the angiogenesis and invasiveness of CSCC.

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References

Bray F, Ferlay J, Soerjomataram I, Siegel R, Torre L, Jemal A . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6):394-424. DOI: 10.3322/caac.21492. View

Crosbie E, Einstein M, Franceschi S, Kitchener H . Human papillomavirus and cervical cancer. Lancet. 2013; 382(9895):889-99. DOI: 10.1016/S0140-6736(13)60022-7. View

Wang X, Cao A, Hou Z, Li X, Gao B . Identification of key classification features of early cervical squamous cell carcinoma. Comput Biol Chem. 2021; 93:107531. DOI: 10.1016/j.compbiolchem.2021.107531. View

Li H, Wu X, Cheng X . Advances in diagnosis and treatment of metastatic cervical cancer. J Gynecol Oncol. 2016; 27(4):e43. PMC: 4864519. DOI: 10.3802/jgo.2016.27.e43. View

Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh J, Comber H . Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013; 49(6):1374-403. DOI: 10.1016/j.ejca.2012.12.027. View

Tewari K, Sill M, Long 3rd H, Penson R, Huang H, Ramondetta L . Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014; 370(8):734-43. PMC: 4010094. DOI: 10.1056/NEJMoa1309748. View

Sozzani R, Maggio C, Varotto S, Canova S, Bergounioux C, Albani D . Interplay between Arabidopsis activating factors E2Fb and E2Fa in cell cycle progression and development. Plant Physiol. 2006; 140(4):1355-66. PMC: 1435807. DOI: 10.1104/pp.106.077990. View

Sun C, Li S, Hu W, Zhang J, Zhou Q, Liu C . RETRACTED: Comprehensive Analysis of the Expression and Prognosis for E2Fs in Human Breast Cancer. Mol Ther. 2019; 27(6):1153-1165. PMC: 6554685. DOI: 10.1016/j.ymthe.2019.03.019. View

Gaubatz S, Lindeman G, Ishida S, Jakoi L, Nevins J, Livingston D . E2F4 and E2F5 play an essential role in pocket protein-mediated G1 control. Mol Cell. 2000; 6(3):729-35. DOI: 10.1016/s1097-2765(00)00071-x. View

10.

Swiatnicki M, Andrechek E . Metastasis is altered through multiple processes regulated by the E2F1 transcription factor. Sci Rep. 2021; 11(1):9502. PMC: 8097008. DOI: 10.1038/s41598-021-88924-y. View

11.

Ertosun M, Hapil F, Osman Nidai O . E2F1 transcription factor and its impact on growth factor and cytokine signaling. Cytokine Growth Factor Rev. 2016; 31:17-25. DOI: 10.1016/j.cytogfr.2016.02.001. View

12.

Manickavinayaham S, Velez-Cruz R, Biswas A, Chen J, Guo R, Johnson D . The E2F1 transcription factor and RB tumor suppressor moonlight as DNA repair factors. Cell Cycle. 2020; 19(18):2260-2269. PMC: 7513849. DOI: 10.1080/15384101.2020.1801190. View

13.

Santos M, Martinez-Fernandez M, Duenas M, Garcia-Escudero R, Alfaya B, Villacampa F . In vivo disruption of an Rb-E2F-Ezh2 signaling loop causes bladder cancer. Cancer Res. 2014; 74(22):6565-6577. PMC: 4233185. DOI: 10.1158/0008-5472.CAN-14-1218. View

14.

Shackney S, Chowdhury S, Schwartz R . A Novel Subset of Human Tumors That Simultaneously Overexpress Multiple E2F-responsive Genes Found in Breast, Ovarian, and Prostate Cancers. Cancer Inform. 2014; 13(Suppl 5):89-100. PMC: 4221091. DOI: 10.4137/CIN.S14062. View

15.

Tu S, Zhang H, Yang X, Wen W, Song K, Yu X . Screening of cervical cancer-related hub genes based on comprehensive bioinformatics analysis. Cancer Biomark. 2021; 32(3):303-315. DOI: 10.3233/CBM-203262. View

16.

Meng W, Meng J, Jiang H, Feng X, Wei D, Ding Q . FKBP4 Accelerates Malignant Progression of Non-Small-Cell Lung Cancer by Activating the Akt/mTOR Signaling Pathway. Anal Cell Pathol (Amst). 2020; 2020:6021602. PMC: 7737458. DOI: 10.1155/2020/6021602. View

17.

Yang W, Moon H, Kim H, Choi E, Yu M, Noh D . Proteomic approach reveals FKBP4 and S100A9 as potential prediction markers of therapeutic response to neoadjuvant chemotherapy in patients with breast cancer. J Proteome Res. 2011; 11(2):1078-88. DOI: 10.1021/pr2008187. View

18.

Zong S, Jiao Y, Liu X, Mu W, Yuan X, Qu Y . FKBP4 integrates FKBP4/Hsp90/IKK with FKBP4/Hsp70/RelA complex to promote lung adenocarcinoma progression via IKK/NF-κB signaling. Cell Death Dis. 2021; 12(6):602. PMC: 8192522. DOI: 10.1038/s41419-021-03857-8. View

19.

Mange A, Coyaud E, Desmetz C, Laurent E, Beganton B, Coopman P . FKBP4 connects mTORC2 and PI3K to activate the PDK1/Akt-dependent cell proliferation signaling in breast cancer. Theranostics. 2019; 9(23):7003-7015. PMC: 6815969. DOI: 10.7150/thno.35561. View

20.

Karar J, Maity A . PI3K/AKT/mTOR Pathway in Angiogenesis. Front Mol Neurosci. 2011; 4:51. PMC: 3228996. DOI: 10.3389/fnmol.2011.00051. View