甲基轉移酶在攝護腺癌惡化過程作用機制之研究

Role of Methyltransferase in prostate cancer progression

蔡心浩(Hsin-Hao Tsai)

指導教授 ： 李明學

國立臺灣大學/醫學院/生物化學暨分子生物學研究所/碩士(2017年)

https://doi.org/10.6342/NTU201702324

摘要

雄激素剝奪治療（ADT）已被廣泛用於前列腺癌（PCa）治療。雖然大多數患者對ADT有良好的早期反應，但是到治療後期，攝護腺癌細胞通常對該療法產生抗性，並且轉變成為具有高轉移潛力的「抗荷爾蒙療法之轉移性攝護腺癌」。 攝護腺癌轉化為抗賀爾蒙療法攝護腺癌（CRPC）的分子機制仍然尚未明瞭。在這項研究中，我分析了表觀遺傳修飾的失調是否在攝護腺癌轉變為抗賀爾蒙療法過程中扮演角色。結果表明，CRPC細胞中甲基轉移酶H的表達水平明顯高於其他組蛋白甲基轉移酶。 甲基轉移酶H剃除顯著降低CRPC細胞的生長和侵襲能力，同時也降低雄激素受體 (AR)和前列腺特異抗體 (PSA)的蛋白表現量。另外，甲基轉移酶H剃除恢復了抗賀爾蒙療法攝護腺癌細胞的雄激素敏感性。 過度表達甲基轉移酶H會促進雄激素依賴性前列腺癌細胞的生長和侵襲能力，並且在雄激素剝奪條件下增加AR和PSA的表達。 除此之外，過表達甲基轉移酶H的 LNCaP細胞生長在雙氫睪酮 (DHT)的刺激下並沒有進一步的提升。這些實驗結果一起證實了甲基轉移酶H會通過促進雄激素受體信號參與攝護腺癌轉變為抗賀爾蒙療法的過程。

關鍵字

抗荷爾蒙療法之攝護腺癌 ； 組蛋白甲基化 ； 甲基轉移? ； 雄激素訊息傳遞路徑

並列摘要

Androgen-deprivation therapy (ADT) has been frequently used for prostate cancer (PCa) therapy. Although most patients have a good early response to ADT, however, PCa cells often acquire resistance to this therapy and become “castration resistant” with a high potential of metastasis. The molecular mechanisms how PCa transforms to castration-resistant prostate cancer (CRPC) are still elusive. In this study, I investigated whether dysregulation of epigenetic modifications played a role in the PCa progression to a castration-resistant stage. The results showed that the expression levels of Methyltransferase H (MTH) rather than the other histone methyltransferases were significantly increased in CRPC cells. MTH silencing significantly reduced the growth and invasion abilities of CRPC cells, and decreased the protein levels of AR and PSA. Moreover, MTH knockdown restored the androgen sensitivity of castration-resistant prostate cancer cells. Overexpression of MTH promoted the growth and invasion ability of androgen-dependent prostate cancer cells, and increased the expression of AR and PSA in an androgen-deprivation condition. DHT, a potent androgen, had no further stimulation effect on the growth of MTH-overexpressing LNCaP cells. The results together indicate that MTH is involved in castration-resistant prostate cancer progression via up-regulating AR signaling.

並列關鍵字

castration-resistant prostate cancer ； histone methyltransferase ； Methyltransferase H ； androgen receptor signaling pathway

參考文獻

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30

2. Welfare 台MoHa. 104年主要死因統計結果分析. 104年(2015)

3. Shen MM, Abate-Shen C. Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev 2010;24:1967-2000

4. Wang Q, Li W, Liu XS, Carroll JS, Janne OA, Keeton EK, et al. A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. Mol Cell 2007;27:380-92

5. Amaral TM, Macedo D, Fernandes I, Costa L. Castration-resistant prostate cancer: mechanisms, targets, and treatment. Prostate Cancer 2012;2012:327253