Hypermethylation of the GRHL2 promoter region is associated with ovarian endometriosis

in Reproduction
Authors:
Yali HaoDepartment of Gynecology, Hebei Medical University Fourth Hospital, Shijiazhuang, Hebei, People’s Republic of China
Department of Molecular Biology, Hebei Medical University Fourth Hospital, Shijiazhuang, Hebei, People’s Republic of China
Department of Reproductive Medicine, Hebei Medical University Fourth Hospital, Shijiazhuang, Hebei, People’s Republic of China

Search for other papers by Yali Hao in
Current site
Google Scholar
PubMedClose
,
Yan LiDepartment of Molecular Biology, Hebei Medical University Fourth Hospital, Shijiazhuang, Hebei, People’s Republic of China

Search for other papers by Yan Li in
Current site
Google Scholar
PubMedClose
,
Jianlei WuDepartment of Gynecology, Hebei Medical University Fourth Hospital, Shijiazhuang, Hebei, People’s Republic of China
Department of Gynecological Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China

Search for other papers by Jianlei Wu in
Current site
Google Scholar
PubMedClose
,
Na HaoDepartment of Gynecology, Hebei Medical University Fourth Hospital, Shijiazhuang, Hebei, People’s Republic of China

Search for other papers by Na Hao in
Current site
Google Scholar
PubMedClose
,
Yuzhen QinDepartment of Gynecology, Hebei Medical University Fourth Hospital, Shijiazhuang, Hebei, People’s Republic of China

Search for other papers by Yuzhen Qin in
Current site
Google Scholar
PubMedClose
,
Haibo zhangDepartment of Gynecology, Hebei Medical University Fourth Hospital, Shijiazhuang, Hebei, People’s Republic of China

Search for other papers by Haibo zhang in
Current site
Google Scholar
PubMedClose
,
Wei ZhaoDepartment of Gynecology, Hebei Medical University Fourth Hospital, Shijiazhuang, Hebei, People’s Republic of China

Search for other papers by Wei Zhao in
Current site
Google Scholar
PubMedClose
, and
Shan KangDepartment of Gynecology, Hebei Medical University Fourth Hospital, Shijiazhuang, Hebei, People’s Republic of China

Search for other papers by Shan Kang in
Current site
Google Scholar
PubMedClose
https://orcid.org/0000-0001-7790-2393
View More View Less

Correspondence should be addressed to S Kang; Email: ksjq62cn@sina.com
DOI:
https://doi.org/10.1530/REP-21-0383
Volume/Issue:
Volume 163: Issue 6
Page Range:
379–386
Article Type:
Research Article
Online Publication Date:
19 May 2022
Copyright:
© Society for Reproduction and Fertility 2022
Restricted access

USD  $0.01
USD  $0.01

USD  $0.01
USD  $0.01

USD  $0.01
USD  $0.01

USD  $0.01
USD  $0.01

USD  $0.01
USD  $0.01

USD  $0.01
USD  $0.01

USD  $0.01
USD  $0.01

USD  $1.00
USD  $1.00

Abnormal gene expression caused by epigenetic changes, including DNA methylation, is associated with the development and progression of endometriosis. Grainyhead-like 2 gene (GRHL2), a suppressor of epithelial–mesenchymal transition, has been suggested to be associated with the occurrence, progression and poor survival of a variety of cancers. Although endometriosis is a benign disease, it has the biological behaviour of migration and invasion as malignant tumor. This study aims to determine whether the abnormal expression of the GRHL2 caused by aberrant methylation of its promoter is associated with the pathogenesis of ovarian endometriosis. Our results demonstrated that GRHL2 promoter region was significantly hypermethylated in the ectopic endometrium of patients with ovarian endometriosis compared with the normal endometrium of control patients. In contrast, the levels of GRHL2 mRNA and protein were significantly lower in the ectopic endometrium than in the control endometrium. Correlation analysis showed the methylation levels of GRHL2 were significantly negatively correlated with the mRNA expression of GRHL2. Moreover, the in vitro results suggested that the knockdown of GRHL2 could significantly increase the invasion and migration ability of EECs and may promote ZEB1 and vimentin expression while decreasing the expression of E-cadherin in EECs. Taken together, these results suggest that the low expression of GRHL2 caused by hypermethylation of the GRHL2 promoter is associated with ovarian endometriosis. The knockdown of GRHL2 may be involved in the occurrence of endometriosis by increasing EEC migration and invasion. This study provides more evidence for the hypothesis that endometriosis may be an epigenetic regulatory disorder.

Reproduction is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 72 36 5
PDF Downloads 78 38 7

 

  • Collapse
  • Expand
Print ISSN:
1470-1626
Online ISSN:
1741-7899

  • Breitling LP, Yang R, Korn B, Burwinkel B & Brenner H 2011 Tobacco-smoking-related differential DNA methylation: 27K discovery and replication. American Journal of Human Genetics 88 450–457. (https://doi.org/10.1016/j.ajhg.2011.03.003)

    • Search Google Scholar
    • Export Citation

  • Chung VY, Tan TZ, Tan M, Wong MK, Kuay KT, Yang Z, Ye J, Muller J, Koh CM & Guccione E et al.2016 GRHL2-miR-200-ZEB1 maintains the epithelial status of ovarian cancer through transcriptional regulation and histone modification. Scientific Reports 6 19943. (https://doi.org/10.1038/srep19943)

    • Search Google Scholar
    • Export Citation

  • Chung VY, Tan TZ, Ye J, Huang RL, Lai HC, Kappei D, Wollmann H, Guccione E & Huang RY 2019 The role of GRHL2 and epigenetic remodeling in epithelial-mesenchymal plasticity in ovarian cancer cells. Communications Biology 2 272. (https://doi.org/10.1038/s42003-019-0506-3)

    • Search Google Scholar
    • Export Citation

  • Cieply B, Riley P, Pifer PM, Widmeyer J, Addison JB, Ivanov AV, Denvir J & Frisch SM 2012 Suppression of the epithelial–mesenchymal transition by Grainyhead-like-2. Cancer Research 72 2440–2453. (https://doi.org/10.1158/0008-5472.CAN-11-4038)

    • Search Google Scholar
    • Export Citation

  • Cieply B, Farris J, Denvir J, Ford HL & Frisch SM 2013 Epithelial–mesenchymal transition and tumor suppression are controlled by a reciprocal feedback loop between ZEB1 and Grainyhead-like-2. Cancer Research 73 6299–6309. (https://doi.org/10.1158/0008-5472.CAN-12-4082)

    • Search Google Scholar
    • Export Citation

  • Dompe N, Rivers CS, Li L, Cordes S, Schwickart M, Punnoose EA, Amler L, Seshagiri S, Tang J & Modrusan Z et al.2011 A whole-genome RNAi screen identifies an 8q22 gene cluster that inhibits death receptor-mediated apoptosis. PNAS 108 E943–E951. (https://doi.org/10.1073/pnas.1100132108)

    • Search Google Scholar
    • Export Citation

  • Frisch SM, Farris JC & Pifer PM 2017 Roles of Grainyhead-like transcription factors in cancer. Oncogene 36 6067–6073. (https://doi.org/10.1038/onc.2017.178)

    • Search Google Scholar
    • Export Citation

  • Gaetje R, Kotzian S, Herrmann G, Baumann R & Starzinski-Powitz A 1997 Nonmalignant epithelial cells, potentially invasive in human endometriosis, lack the tumor suppressor molecule E-cadherin. American Journal of Pathology 150 461–467.

    • Search Google Scholar
    • Export Citation

  • Giudice LC & Kao LC 2004 Endometriosis. Lancet 364 1789–1799. (https://doi.org/10.1016/S0140-6736(0417403-5)

  • He X, Liu N, Mu T, Lu D, Jia C, Wang S, Yin C, Liu L, Zhou L & Huang X et al.2020 Oestrogen induces epithelial-mesenchymal transition in endometriosis via circ_0004712/miR-148a-3p sponge function. Journal of Cellular and Molecular Medicine 24 9658–9666. (https://doi.org/10.1111/jcmm.15495)

    • Search Google Scholar
    • Export Citation

  • Henriett B, Szabó PM, Roy NM, Fabio R, Kalman K, Lorna M, Hala G, Dina B, Attila P & Yousef GM 2014 Integrative bioinformatics analysis reveals new prognostic biomarkers of clear cell renal cell carcinoma. Clinical Chemistry 10 1314–1326. (https://doi.org/10.1373/clinchem.2014.225854)

    • Search Google Scholar
    • Export Citation

  • Hsiao KY, Wu MH & Tsai SJ 2017 Epigenetic regulation of the pathological process in endometriosis. Reproductive Medicine and Biology 16 314–319. (https://doi.org/10.1002/rmb2.12047)

    • Search Google Scholar
    • Export Citation

  • Hu F, He Z, Sun C & Rong D 2019 Knockdown of GRHL2 inhibited proliferation and induced apoptosis of colorectal cancer by suppressing the PI3K/Akt pathway. Gene 700 96–104. (https://doi.org/10.1016/j.gene.2019.03.051)

    • Search Google Scholar
    • Export Citation

  • Juanqing L, Hailan Y, Xiangwei F, Tao Z, Junyan M, Jianhong Z, Jun L & Jianhua Y 2019 Relationship between the methylation levels of Twist gene and pathogenesis of endometriosis. Cellular and Molecular Biology 65 94–100. (https://doi.org/10.14715/cmb/2019.65.3.14)

    • Search Google Scholar
    • Export Citation

  • Kang X, Chen W, Kim RH, Kang MK & Park NH 2009 Regulation of the hTERT promoter activity by MSH2, the hnRNPs K and D, and GRHL2 in human oral squamous cell carcinoma cells. Oncogene 28 565–574. (https://doi.org/10.1038/onc.2008.404)

    • Search Google Scholar
    • Export Citation

  • Kang X, Li W, Liu W, Liang H, Deng J, Wong CC, Zhao S, Kang W, To KF & Chiu PWY et al.2021 LIMK1 promotes peritoneal metastasis of gastric cancer and is a therapeutic target. Oncogene 40 3422–3433. (https://doi.org/10.1038/s41388-021-01656-1)

    • Search Google Scholar
    • Export Citation

  • Lagana AS, Vitale SG, Salmeri FM, Triolo O, Ban Frangez H, Vrtacnik-Bokal E, Stojanovska L, Apostolopoulos V, Granese R & Sofo V 2017 Unus pro omnibus, omnes pro uno: a novel, evidence-based, unifying theory for the pathogenesis of endometriosis. Medical Hypotheses 103 10–20. (https://doi.org/10.1016/j.mehy.2017.03.032)

    • Search Google Scholar
    • Export Citation

  • Laudanski P, Charkiewicz R, Kuzmicki M, Szamatowicz J, Swiatecka J, Mroczko B & Niklinski J 2014 Profiling of selected angiogenesis-related genes in proliferative eutopic endometrium of women with endometriosis. European Journal of Obstetrics, Gynecology, and Reproductive Biology 172 85–92. (https://doi.org/10.1016/j.ejogrb.2013.10.007)

    • Search Google Scholar
    • Export Citation

  • Li Y, An D, Guan YX & Kang S 2017 Aberrant methylation of the E-cadherin gene promoter region in endometrium and ovarian endometriotic cysts of patients with ovarian endometriosis. Gynecologic and Obstetric Investigation 82 78–85. (https://doi.org/10.1159/000445293)

    • Search Google Scholar
    • Export Citation

  • Matsuzaki S & Darcha C 2012 Epithelial to mesenchymal transition-like and mesenchymal to epithelial transition-like processes might be involved in the pathogenesis of pelvic endometriosis. Human Reproduction 27 712–721. (https://doi.org/10.1093/humrep/der442)

    • Search Google Scholar
    • Export Citation

  • Nasu K, Kawano Y, Tsukamoto Y, Takano M, Takai N, Li H, Furukawa Y, Abe W, Moriyama M & Narahara H 2011 Aberrant DNA methylation status of endometriosis: epigenetics as the pathogenesis, biomarker and therapeutic target. Journal of Obstetrics and Gynaecology Research 37 683–695. (https://doi.org/10.1111/j.1447-0756.2011.01663.x)

    • Search Google Scholar
    • Export Citation

  • Owusu-Akyaw A, Krishnamoorthy K, Goldsmith LT & Morelli SS 2019 The role of mesenchymal-epithelial transition in endometrial function. Human Reproduction Update 25 114–133. (https://doi.org/10.1093/humupd/dmy035)

    • Search Google Scholar
    • Export Citation

  • Paltoglou S, Das R, Townley SL, Hickey TE, Tarulli GA, Coutinho I, Fernandes R, Hanson AR, Denis I & Carroll JS et al.2017 Novel androgen receptor coregulator GRHL2 exerts both oncogenic and antimetastatic functions in prostate cancer. Cancer Research 77 3417–3430. (https://doi.org/10.1158/0008-5472.CAN-16-1616)

    • Search Google Scholar
    • Export Citation

  • Pan X, Zhang R, Xie C, Gan M, Yao S, Yao Y, Jin J, Han T, Huang Y & Gong Y et al.2017 GRHL2 suppresses tumor metastasis via regulation of transcriptional activity of RhoG in non-small cell lung cancer. American Journal of Translational Research 9 4217–4226.

    • Search Google Scholar
    • Export Citation

  • Reese RM, Harrison MM & Alarid ET 2019 Grainyhead-like protein 2: the emerging role in hormone-dependent cancers and epigenetics. Endocrinology 160 1275–1288. (https://doi.org/10.1210/en.2019-00213)

    • Search Google Scholar
    • Export Citation

  • Sampson JA 1927 Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. American Journal of Pathology 3 93–110.43.

    • Search Google Scholar
    • Export Citation

  • Schübeler D 2015 Function and information content of DNA methylation. Nature 517 321–326. (https://doi.org/10.1038/nature14192)

  • Shen J, Lv X & Zhang L 2020 GRHL2 acts as an anti-oncogene in bladder cancer by regulating ZEB1 in epithelial-mesenchymal transition (EMT) process. OncoTargets and Therapy 13 2511–2522. (https://doi.org/10.2147/OTT.S239120)

    • Search Google Scholar
    • Export Citation

  • Sofo V, Götte M, Laganà AS, Salmeri FM, Triolo O, Sturlese E, Retto G, Alfa M, Granese R & Abrão MS 2015 Correlation between dioxin and endometriosis: an epigenetic route to unravel the pathogenesis of the disease. Archives of Gynecology and Obstetrics 292 973–986. (https://doi.org/10.1007/s00404-015-3739-5)

    • Search Google Scholar
    • Export Citation

  • Song Y, Xiao L, Fu J, Huang W, Wang Q, Zhang X & Yang S 2014 Increased expression of the pluripotency markers sex-determining region Y-box 2 and Nanog homeobox in ovarian endometriosis. Reproductive Biology and Endocrinology 12 42. (https://doi.org/10.1186/1477-7827-12-42)

    • Search Google Scholar
    • Export Citation

  • Tanaka Y, Kanai F, Tada M, Tateishi R, Sanada M, Nannya Y, Ohta M, Asaoka Y, Seto M & Shiina S et al.2008 Gain of GRHL2 is associated with early recurrence of hepatocellular carcinoma. Journal of Hepatology 49 746–757. (https://doi.org/10.1016/j.jhep.2008.06.019)

    • Search Google Scholar
    • Export Citation

  • Vitale SG, Capriglione S, Peterlunger I, La Rosa VL, Vitagliano A, Noventa M, Valenti G, Sapia F, Angioli R & Lopez S et al.2018 The role of oxidative stress and membrane transport systems during endometriosis: a fresh look at a busy corner. Oxidative Medicine and Cellular Longevity 2018 1–14. (https://doi.org/10.1155/2018/7924021) (7924021)

    • Search Google Scholar
    • Export Citation

  • Wang L, Zhao J, Li Y, Wang Z & Kang S 2019 Genome-wide analysis of DNA methylation in endometriosis using Illumina Human Methylation 450K BeadChips. Molecular Reproduction and Development 86 491–501. (https://doi.org/10.1002/mrd.23127)

    • Search Google Scholar
    • Export Citation

  • Wu YU, Zhang M, Zhang X, Xu Z & Jin W 2016 Methylation status and protein expression of RASSF1A in endometriosis. Oncology Letters 11 4107–4112. (https://doi.org/10.3892/ol.2016.4512)

    • Search Google Scholar
    • Export Citation

  • Xiang J, Fu X, Ran W, Chen X, Hang Z, Mao H & Wang Z 2013 Expression and role of grainyhead-like 2 in gastric cancer. Medical Oncology 30 714. (https://doi.org/10.1007/s12032-013-0714-5)

    • Search Google Scholar
    • Export Citation

  • Xiang J, Fu X, Ran W & Wang Z 2017 Grhl2 reduces invasion and migration through inhibition of TGFbeta-induced EMT in gastric cancer. Oncogenesis 6 e284. (https://doi.org/10.1038/oncsis.2016.83)

    • Search Google Scholar
    • Export Citation

  • Zeitvogel A, Baumann R & Starzinski-Powitz A 2001 Identification of an invasive, N-cadherin-expressing epithelial cell type in endometriosis using a new cell culture model. American Journal of Pathology 159 1839–1852. (https://doi.org/10.1016/S0002-9440(1063030-1)

    • Search Google Scholar
    • Export Citation

  • Zhao J, Wang L, Li Y, Zhao W & Kang S 2019a Hypomethylation of the GSTM1 promoter is associated with ovarian endometriosis. Human Reproduction 34 804–812. (https://doi.org/10.1093/humrep/dez039)

    • Search Google Scholar
    • Export Citation

  • Zhao W, Kang S, Zhao J, Wang L, Cao S & Li Y 2019b Aberrant methylation of the IL-12B promotor region contributes to the risk of developing ovarian endometriosis. Molecular Reproduction and Development 86 632–638. (https://doi.org/10.1002/mrd.23139)

    • Search Google Scholar
    • Export Citation

  • Zhu X, Li Y, Zhou R, Wang N & Kang S 2017 Knockdown of E-cadherin expression of endometrial epithelial cells may activate Wnt/β-catenin pathway in vitro. Archives of Gynecology and Obstetrics 297 117–123. (https://doi.org/10.1007/s00404-017-4560-0)

    • Search Google Scholar
    • Export Citation

  • Zondervan KT, Becker CM, Koga K, Missmer SA, Taylor RN & Vigano P 2018 Endometriosis. Nature Reviews: Disease Primers 4 9. (https://doi.org/10.1038/s41572-018-0008-5)

    • Search Google Scholar
    • Export Citation