CTBP1‑AS upregulation is associated with polycystic ovary syndrome and can be effectively downregulated by cryptotanshinone

Wen,Mingxiao; Dou,Xiaoqing; Zhang,Shuzhen; Wang,Bin; Xu,Jiangyan; Zhang,Wenchao; Wang,Feifei

doi:10.3892/mmr.2022.12761

CTBP1‑AS upregulation is associated with polycystic ovary syndrome and can be effectively downregulated by cryptotanshinone

Authors:
- Mingxiao Wen
- Xiaoqing Dou
- Shuzhen Zhang
- Bin Wang
- Jiangyan Xu
- Wenchao Zhang
- Feifei Wang
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Affiliations: Department of Gynecology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang 310060, P.R. China, Department of Clinical Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang 310060, P.R. China
Published online on: June 1, 2022 https://doi.org/10.3892/mmr.2022.12761
Article Number: 245
Copyright: © Wen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies and primarily presents with hyperandrogenism. Although environmental factors and genetic factors are thought to be the major reason, there still exists a lot of questions need to be answered. High expression of C‑terminal‑binding protein 1 antisense (CTBP1‑AS) was identified as an independent risk factor for PCOS; however, the molecular mechanism of CTBP1‑AS in PCOS regulation is unknown. In the present study, the expression level of CTBP1‑AS was found to be significantly upregulated in patients with PCOS compared with healthy control patients. CTBP1‑AS knockdown was demonstrated to reduce the proliferation and promote the apoptosis of granulosa tumor cells in vitro. It was also identified that the two core catalytic subunits of Polycomb repressive complex 2 (enhancer of zeste homolog 2 and embryonic and ectoderm development protein) interacted with CTBP1‑AS in primary granulosa cells and KGN cells. In addition, cryptotanshinone treatment was demonstrated to effectively downregulate CTBP1‑AS expression level. Data from the present study suggested a pathophysiological role of CTBP1‑AS in PCOS and may provide a new potential target for PCOS treatment.

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1	Mortada R and Williams T: Metabolic syndrome: Polycystic ovary syndrome. FP Essent. 435:30–42. 2015.PubMed/NCBI
2	Hardiman P, Pillay OS and Atiomo W: Polycystic ovary syndrome and endometrial carcinoma. Lancet. 361:1810–1812. 2003. View Article : Google Scholar : PubMed/NCBI
3	Akgül S, Düzçeker Y, Kanbur N and Derman O: Do different diagnostic criteria impact polycystic ovary syndrome diagnosis for adolescents? J Pediatr Adolesc Gynecol. 31:258–262. 2018. View Article : Google Scholar : PubMed/NCBI
4	Goodarzi MO, Dumesic DA, Chazenbalk G and Azziz R: Polycystic ovary syndrome: Etiology, pathogenesis and diagnosis. Nat Rev Endocrinol. 7:219–231. 2011. View Article : Google Scholar : PubMed/NCBI
5	Asunción M, Calvo RM, Millán JL, Sancho J, Avila S and Escobar-Morreale HF: A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab. 85:2434–2438. 2000. View Article : Google Scholar : PubMed/NCBI
6	Amiri M, Tehrani FR, Bidhendi-Yarandi R, Behboudi-Gandevani S, Azizi F and Carmina E: Relationships between biochemical markers of hyperandrogenism and metabolic parameters in women with polycystic ovary syndrome: A systematic review and meta-analysis. Horm Metab Res. 51:22–34. 2019. View Article : Google Scholar : PubMed/NCBI
7	Fitzgerald S, DiVasta A and Gooding H: An update on PCOS in adolescents. Curr Opin Pediatr. 30:459–465. 2018. View Article : Google Scholar : PubMed/NCBI
8	Szydlarska D, Machaj M and Jakimiuk A: History of discovery of polycystic ovary syndrome. Adv Clin Exp Med. 26:555–558. 2017. View Article : Google Scholar : PubMed/NCBI
9	Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, : Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 81:19–25. 2004. View Article : Google Scholar
10	Neven ACH, Laven J, Teede HJ and Boyle JA: A summary on polycystic ovary syndrome: Diagnostic criteria, prevalence, clinical manifestations, and management according to the latest international guidelines. Semin Reprod Med. 36:5–12. 2018. View Article : Google Scholar : PubMed/NCBI
11	Wang R and Mol BWJ: The Rotterdam criteria for polycystic ovary syndrome: Evidence-based criteria? Hum Reprod. 32:261–264. 2017. View Article : Google Scholar : PubMed/NCBI
12	Liu Z, Hao C, Song D, Zhang N, Bao H and Qu Q: Androgen receptor coregulator CTBP1-AS is associated with polycystic ovary syndrome in Chinese women: A preliminary study. Reprod Sci. 22:829–837. 2015. View Article : Google Scholar : PubMed/NCBI
13	Patel S: Polycystic ovary syndrome (PCOS), an inflammatory, systemic, lifestyle endocrinopathy. J Steroid Biochem Mol Biol. 182:27–36. 2018. View Article : Google Scholar : PubMed/NCBI
14	Sung YA, Oh JY, Chung H and Lee H: Hyperandrogenemia is implicated in both the metabolic and reproductive morbidities of polycystic ovary syndrome. Fertil Steril. 101:840–845. 2014. View Article : Google Scholar : PubMed/NCBI
15	Norman RJ, Dewailly D, Legro RS and Hickey TE: Polycystic ovary syndrome. Lancet. 370:685–697. 2007. View Article : Google Scholar : PubMed/NCBI
16	Gelmann EP: Molecular biology of the androgen receptor. J Clin Oncol. 20:3001–3015. 2002. View Article : Google Scholar : PubMed/NCBI
17	Meng D, Yang S, Wan X, Zhang Y, Huang W, Zhao P, Li T, Wang L, Huang Y, Li T and Li Y: A transcriptional target of androgen receptor, miR-421 regulates proliferation and metabolism of prostate cancer cells. Int J Biochem Cell Biol. 73:30–40. 2016. View Article : Google Scholar : PubMed/NCBI
18	Takayama KI: Splicing factors have an essential role in prostate cancer progression and androgen receptor signaling. Biomolecules. 9:1312019. View Article : Google Scholar : PubMed/NCBI
19	Baculescu N: The role of androgen receptor activity mediated by the CAG repeat polymorphism in the pathogenesis of PCOS. J Med Life. 6:18–25. 2013.PubMed/NCBI
20	Bevan CL, Hoare S, Claessens F, Heery DM and Parker MG: The AF1 and AF2 domains of the androgen receptor interact with distinct regions of SRC1. Mol Cell Biol. 19:8383–8392. 1999. View Article : Google Scholar : PubMed/NCBI
21	Xu J, Qiu Y, DeMayo FJ, Tsai SY, Tsai MJ and O'Malley BW: Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene. Science. 279:1922–1925. 1998. View Article : Google Scholar : PubMed/NCBI
22	Cheng S, Brzostek S, Lee SR, Hollenberg AN and Balk SP: Inhibition of the dihydrotestosterone-activated androgen receptor by nuclear receptor corepressor. Mol Endocrinol. 16:1492–1501. 2002. View Article : Google Scholar : PubMed/NCBI
23	Berrevoets CA, Umar A, Trapman J and Brinkmann AO: Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR). Biochem J. 379:731–738. 2004. View Article : Google Scholar : PubMed/NCBI
24	Takayama KI, Horie-Inoue K, Katayama S, Suzuki T, Tsutsumi S, Ikeda K, Urano T, Fujimura T, Takagi K, Takahashi S, et al: Androgen-responsive long noncoding RNA CTBP1-AS promotes prostate cancer. EMBO J. 32:1665–1680. 2013. View Article : Google Scholar : PubMed/NCBI
25	Takayama K, Tsutsumi S, Katayama S, Okayama T, Horie-Inoue K, Ikeda K, Urano T, Kawazu C, Hasegawa A, Ikeo K, et al: Integration of cap analysis of gene expression and chromatin immunoprecipitation analysis on array reveals genome-wide androgen receptor signaling in prostate cancer cells. Oncogene. 30:619–630. 2011. View Article : Google Scholar : PubMed/NCBI
26	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
27	Czermin B, Melfi R, McCabe D, Seitz V, Imhof A and Pirrotta V: Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell. 111:185–196. 2002. View Article : Google Scholar : PubMed/NCBI
28	Montgomery ND, Yee D, Chen A, Kalantry S, Chamberlain SJ, Otte AP and Magnuson T: The murine polycomb group protein Eed is required for global histone H3 lysine-27 methylation. Curr Biol. 15:942–947. 2005. View Article : Google Scholar : PubMed/NCBI
29	Ji XY, Tan B and Zhu YZ: Salvia miltiorrhiza and ischemic diseases. Acta Pharmacol Sin. 21:1089–1094. 2000.PubMed/NCBI
30	Wang X, Morris-Natschke SL and Lee KH: New developments in the chemistry and biology of the bioactive constituents of Tanshen. Med Res Rev. 27:133–148. 2007. View Article : Google Scholar : PubMed/NCBI
31	Havelock JC, Rainey WE and Carr BR: Ovarian granulosa cell lines. Mol Cell Endocrinol. 228:67–78. 2004. View Article : Google Scholar : PubMed/NCBI
32	Morita Y and Tilly JL: Oocyte apoptosis: Like sand through an hourglass. Dev Biol. 213:1–17. 1999. View Article : Google Scholar : PubMed/NCBI
33	Buccione R, Schroeder AC and Eppig JJ: Interactions between somatic cells and germ cells throughout mammalian oogenesis. Biol Reprod. 43:543–547. 1990. View Article : Google Scholar : PubMed/NCBI
34	Erickson GF, Magoffin DA, Garzo VG, Cheung AP and Chang RJ: Granulosa cells of polycystic ovaries: Are they normal or abnormal? Hum Reprod. 7:293–299. 1992. View Article : Google Scholar : PubMed/NCBI
35	Jakimiuk AJ, Weitsman SR, Navab A and Magoffin DA: Luteinizing hormone receptor, steroidogenesis acute regulatory protein, and steroidogenic enzyme messenger ribonucleic acids are overexpressed in thecal and granulosa cells from polycystic ovaries. J Clin Endocrinol Metab. 86:1318–1323. 2001. View Article : Google Scholar : PubMed/NCBI
36	Liu Q, Wang G, Li Q, Jiang W, Kim JS, Wang R, Zhu S, Wang X, Yan L, Yi Y, et al: Polycomb group proteins EZH2 and EED directly regulate androgen receptor in advanced prostate cancer. Int J Cancer. 145:415–426. 2019. View Article : Google Scholar : PubMed/NCBI
37	Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X, Wang W, Wu L, Li J, Hu M, et al: An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. Cancer Cell. 17:443–454. 2010. View Article : Google Scholar : PubMed/NCBI