2017年10月2日, 國際學術權威刊物自然出版集團旗下子刊、腫瘤學重要學術期刊《Oncogene》雜誌線上發表了南京大學模式動物研究所嚴俊課題組在研究惡性前列腺癌形成與維持的研究進展, 研究成果題為《A regulatory circuit HP1γ/miR-451a/c-Myc promotes prostate cancer progression》。 研究揭示了惡性前列腺癌細胞中c-Myc癌蛋白如何維持自身高表達水準的新機制。 南京大學博士研究生常存傑為論文第一作者, 嚴俊副教授為論文通信作者。
前列腺癌是男性最常見的惡性腫瘤之一。 2016年, 美國的前列腺癌的估計新發病病例占男性腫瘤的21%, 而其導致的死亡病例占男性腫瘤死亡例數的8%。 雖然東亞人群中前列腺癌的發病率遠低於北美人群的前列腺癌發病率,
c-Myc癌基因在前列腺癌中呈現DNA拷貝數擴展和/或過表達現象, 但是仍然有一部分人類前列腺癌組織中只存在高水準c-Myc蛋白, 而沒有DNA擴增和過表達現象, 暗示了可能存在其它的調控 c-Myc表達的機制。 課題組研究人員首先發現並驗證了一個新的受到 c-Myc直接調控的靶基因, 其編碼組蛋白H3K9me2/3結合蛋白----異染色質蛋白1γ(HP1γ)。 由於先前兩篇獨立的科研報導呈現了在前列腺癌中HP1γ表達改變情況上截然相反的結果,
原文連結:
原文摘要:
Heterochromatin protein 1γ (HP1γ) has been implicated in carcinogenesis of various cancer types. However, the role of HP1γin prostate cancer (PCa) progression and the underlying molecular mechanisms remain largely unknown. We found that HP1γ is upregulated in PCa and elevated levels of HP1γ in PCa predict poor outcome. In addition, depletion of HP1γ in PCa cells not only repressed proliferation and induced apoptosis but also impaired tumorigenicity. We also found that c-Myc was capable of upregulating HP1γ by directly binding to the E-box element in the first intron of HP1γ gene, and the upregulated HP1γ, in turn, repressed the expression of miR-451a by enhancing H3K9 methylation at the promoter region of miR-451a. Furthermore, reduction of miR-451a significantly reversed HP1γ loss-induced PCa cell apoptosis, wheras miR-451a overexpression repressed cell survival by targeting and downregulating c-Myc. The association among c-Myc, HP1γ and miR-451a was further confirmed in human clinical samples. Therefore, we propose that an HP1γ/miR-451a/c-Myc regulatory circuitry exists in PCa cells and this circuit has a crucial role in PCa progression.