厦门大学生科院教授JCI发文:癌转移新机制
生物通 · 2017/05/02
来自厦门大学生科院,细胞应激生物学国家重点实验室的研究人员发表了题为“Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis”的文章,揭示FoxO3是乳腺癌转移的重要抑制分子,阐明了geminin作为癌基因的分子基础,为发现乳腺癌的转移标志物提供重要的理论依据。


来自厦门大学生科院,细胞应激生物学国家重点实验室的研究人员发表了题为“Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis”的文章,揭示FoxO3是乳腺癌转移的重要抑制分子,阐明了geminin作为癌基因的分子基础,为发现乳腺癌的转移标志物提供重要的理论依据。

这一研究成果公布在Journal of Clinical Investigation杂志上,文章的通讯作者为尤涵教授,第一作者为张蕾助理教授。

Geminin广泛参与调控基因转录和染色质重塑,在胚胎发育中有重要地位; geminin还是DNA重复复制(DNA re-replication)的负向调控分子,其功能的丧失导致基因组不稳定性。然而,与“维持基因组稳定性”功能相矛盾的是:在许多人类肿瘤中geminin呈现高表达,并且geminin水平越高的肿瘤其预后越差,提示geminin可能具有癌基因的功能,其机理却一直是个谜。

尤涵研究团队发现,geminin调节PI3K/AKT通路FoxO转录因子的转录活性,进而调控乳腺癌细胞的侵袭转移能力。PI3K/AKT通路在人类肿瘤中的基因突变频率最高,绝大多数肿瘤中存在PI3K/AKT的过度激活。FoxO转录因子的转录活性受PI3K/AKT的负向调控,该家族主要包括FoxO1、FoxO3和FoxO4,是调控细胞应激反应的核心分子,同时也是组织特异性的抑癌分子。目前关于“FoxO家族分子在肿瘤转移中的功能”报道极少。

这项研究发现,FoxO3功能丧失能够显著增强乳腺癌细胞在体内体外的转移潜能,其分子机理为FoxO3转录激活Dicer,进而调控miRNAs的成熟和乳腺癌转移。 “FoxO的乙酰化/去乙酰化修饰对其转录活性的影响”一直是FoxO领域的关注焦点和争论热点。该研究进一步发现geminin能够特异性地介导FoxO3和HDAC3的相互作用,而HDAC3对FoxO3的去乙酰化修饰显著抑制了FoxO3对Dicer的转录激活,进而促进肿瘤转移。在临床乳腺癌样本中,FoxO3表达水平与Dicer水平显著正相关。在grade II 和grade III乳腺癌样本中,FoxO与Dicer均明显下调;geminin与HDAC3则呈现高表达水平,并且与Dicer表达水平呈显著负相关。

这项不仅揭示FoxO3是乳腺癌转移的重要抑制分子,同时还阐明geminin作为癌基因的分子基础,为发现乳腺癌的转移标志物提供重要的理论依据。

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  • Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis

    Geminin expression is essential for embryonic development and the maintenance of chromosomal integrity. In spite of this protective role, geminin is also frequently overexpressed in human cancers and the molecular mechanisms underlying its role in tumor progression remain unclear. The histone deacetylase HDAC3 modulates transcription factors to activate or suppress transcription. Little is known about how HDAC3 specifies substrates for modulation among highly homologous transcription factor family members. Here, we have demonstrated that geminin selectively couples the transcription factor forkhead box O3 (FoxO3) to HDAC3, thereby specifically facilitating FoxO3 deacetylation. We determined that geminin–associated HDAC3 deacetylates FoxO3 to block its transcriptional activity, leading to downregulation of the downstream FoxO3 target Dicer, an RNase that suppresses metastasis. Breast cancer cells depleted of geminin or HDAC3 exhibited poor metastatic potential that was attributed to reduced suppression of the FoxO3-Dicer axis. Moreover, elevated levels of geminin, HDAC3, or both together with decreased FoxO3 acetylation and reduced Dicer expression were detected in aggressive human breast cancer specimens. These results underscore a prominent role for geminin in promoting breast cancer metastasis via the enzyme-substrate–coupling mechanism in HDAC3-FoxO3 complex formation.

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