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The H3K9 Methyltransferase G9a Represses E-cadherin and is Associated with Myometrial Invasion in Endometrial Cancer

  • Translational Research and Biomarkers
  • Published:
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Abstract

Background

Emerging evidence suggests that G9a, a histone methyltransferase, is involved in tumor progression and metastasis. However, the functional significance of G9a in endometrial carcinogenesis has not been defined.

Methods

The differential expression of G9a in cancer and normal tissues was assessed using an array of 28 paired samples. Tissue specimens from 94 patients with endometrial cancer who underwent primary surgery were immunohistochemically evaluated for G9a and E-cadherin expression. To assess the biologic role of G9a in endometrial cancer, G9a was either stably knocked down or knocked down using a tetracycline-controllable system in endometrial cancer cells, followed by functional assays.

Results

Increased G9a expression was identified in endometrial cancer tissues, and its expression was specifically correlated with deep myometrial invasion. Cell invasiveness was inhibited by an RNAi-mediated knockdown of G9a in invasive endometrial cancer cells in vitro and in vivo. An important mediator of G9a-induced tumor invasion is the epigenetic silencing of E-cadherin. Knockdown of G9a restored E-cadherin expression by reducing H3K9me2 levels and decreasing CDH1 promoter DNA methyltransferase recruitment. Knockdown of RNAi-mediated E-cadherin substantially relieved the invasion suppression imposed by G9a suppression. A significant negative correlation between G9a and E-cadherin expression was observed in endometrial cancer (Spearman’s rho, −0.27; P = 0.02).

Conclusions

This study provides the first clear evidence that G9a contributes to endometrial cancer progression. Mechanistic investigations suggest that E-cadherin repression mediates the effects of G9a. Targeting G9a-mediated epigenetic pathway dysregulation may be a therapeutic strategy for endometrial cancers.

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Acknowledgment

The authors thank Dr. Pao-Ling Torng for technical assistance. They also are grateful for the financial support from the National Health Research Institutes of Taiwan, NHRI-EX102-10133BI; the National Science Council, 99-2314-B-002-008-MY; and Far Eastern Memorial Hospital, FEMH-2011-D-008.

Conflict of interest

There are no conflicts of interest.

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Author notes

    Authors and Affiliations

    1. Department of Obstetrics and Gynecology, Far Eastern Memorial Hospital, New Taipei, Taiwan

      Sheng-Mou Hsiao MD

    2. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

      Min-Wei Chen PhD & Lin-Hung Wei MD, PhD

    3. Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan

      Chi-An Chen MD & Lin-Hung Wei MD, PhD

    4. Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan

      Ming-Hsien Chien PhD

    5. Wan Fan Hospital, Taipei Medical University, Taipei, Taiwan

      Ming-Hsien Chien PhD

    6. Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan

      Kuo-Tai Hua PhD

    7. Genomics Research Center, Academia Sinica, Taipei, Taiwan

      Michael Hsiao PhD

    8. Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan

      Min-Liang Kuo PhD

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    1. Sheng-Mou Hsiao MD
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    Correspondence to Lin-Hung Wei MD, PhD.

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    Sheng-Mou Hsiao and Min-Wei Chen have contributed equally.

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    Hsiao, SM., Chen, MW., Chen, CA. et al. The H3K9 Methyltransferase G9a Represses E-cadherin and is Associated with Myometrial Invasion in Endometrial Cancer. Ann Surg Oncol 22 (Suppl 3), 1556–1565 (2015). https://doi.org/10.1245/s10434-015-4379-5

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    • DOI: https://doi.org/10.1245/s10434-015-4379-5

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