组蛋白去乙酰化酶3参与调控Hippo信号通路

Histone Deacetylase 3 Modulates Hippo Signaling Pathway

Hippo信号通路在器官大小、组织再生和肿瘤发生发展等方面发挥重要作用,且它在进化上高度保守。Hippo信号通路的失调和多种癌症密切相关。果蝇中Hippo信号通路上游的级联激酶通过磷酸化效应因子Yki,进而调控Yki和转录因子Sd的结合以及下游靶基因的表达。为了寻找Hippo信号通路新的调控因子,我们以过表达Yki造成果蝇眼睛过度增生的表型为基础,进行修饰因子筛选。通过筛选,我们发现组蛋白去乙酰化酶3(HDAC3)参与调控Hippo信号通路,敲除HDAC3特异性地抑制由过表达Yki引起的组织增生,导致果蝇眼睛变小。之后我们通过免疫荧光染色发现HDAC3的缺失激活了Hippo信号通路,进而影响器官发育。进一步地,我们利用遗传学实验和双萤光素酶报告系统分析探究到HDAC3作用于Sd上游,在体外条件下HDAC3的失活能够显著抑制Sd-Yki转录复合体的转录活性。这为探索Hippo信号通路新的调控机制奠定基础,也为HDAC3抑制剂的抗肿瘤治疗提供新的理论支持。

Hippo signaling pathway is highly conserved in revolution and plays an important role in organ size,tissue regeneration and tumor development.The disorder of Hippo signaling pathway is closely related to a variety of cancers.In Drosophila,the upstream kinase of Hippo signaling pathway phosphorylates the effector Yki,then regulates the binding of Yki to transcription factor Sd and the expression of target genes.In order to find new regulators of Hippo signaling pathway,we carried out a genetic modifier screening based on the phenotype of eye overgrowth caused by overexpression of Yki in Drosophila.Through the screening,we identified that histone deacetylase 3(HDAC3)is the potential suppressor of Hippo signaling pathway.Knockdown of HDAC3 specifically suppressed tissue overgrowth driven by Yki,resulting in the reduced eye size.Then the silence of HDAC3 activated the Hippo signaling pathway and modulated tissue development.Furthermore,the epistasis experiment and dual luciferase reporter assay showed that HDAC3 acts upstream of Sd.The inactivation of HDAC3 significantly inhibited the transcription activity of Sd-Yki transcriptional complex in vitro.The study lays a foundation for exploring the new regulation mechanism of Hippo signaling pathway and provides new theoretical support for the antitumor treatment of HDAC3 inhibitors.