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

Sheng Mou Hsiao, Min Wei Chen, Chi An Chen, Ming Hsien Chien, Kuo Tai Hua, Michael Hsiao, Min Liang Kuo, Lin Hung Wei

研究成果: 雜誌貢獻文章

14 引文 (Scopus)

摘要

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.

原文英語
頁(從 - 到)1556-1565
頁數10
期刊Annals of Surgical Oncology
22
DOIs
出版狀態已發佈 - 十二月 1 2015

指紋

Methyltransferases
Cadherins
Endometrial Neoplasms
RNA Interference
Epigenomics
Neoplasms
Tetracycline
Carcinogenesis
Neoplasm Metastasis
DNA

ASJC Scopus subject areas

  • Surgery
  • Oncology

引用此文

The H3K9 Methyltransferase G9a Represses E-cadherin and is Associated with Myometrial Invasion in Endometrial Cancer. / Hsiao, Sheng Mou; Chen, Min Wei; Chen, Chi An; Chien, Ming Hsien; Hua, Kuo Tai; Hsiao, Michael; Kuo, Min Liang; Wei, Lin Hung.

於: Annals of Surgical Oncology, 卷 22, 01.12.2015, p. 1556-1565.

研究成果: 雜誌貢獻文章

Hsiao, Sheng Mou ; Chen, Min Wei ; Chen, Chi An ; Chien, Ming Hsien ; Hua, Kuo Tai ; Hsiao, Michael ; Kuo, Min Liang ; Wei, Lin Hung. / The H3K9 Methyltransferase G9a Represses E-cadherin and is Associated with Myometrial Invasion in Endometrial Cancer. 於: Annals of Surgical Oncology. 2015 ; 卷 22. 頁 1556-1565.
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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.",
author = "Hsiao, {Sheng Mou} and Chen, {Min Wei} and Chen, {Chi An} and Chien, {Ming Hsien} and Hua, {Kuo Tai} and Michael Hsiao and Kuo, {Min Liang} and Wei, {Lin Hung}",
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AU - Hsiao, Sheng Mou

AU - Chen, Min Wei

AU - Chen, Chi An

AU - Chien, Ming Hsien

AU - Hua, Kuo Tai

AU - Hsiao, Michael

AU - Kuo, Min Liang

AU - Wei, Lin Hung

PY - 2015/12/1

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N2 - 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.

AB - 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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