Sun Lidong, Kokura Kenji, Izumi Victoria, Koomen John M, Seto Edward, Chen Jiandong, Fang Jia
Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
EMBO Rep. 2015 Jun;16(6):689-99. doi: 10.15252/embr.201439792. Epub 2015 Apr 13.
As a critical developmental process, epithelial-mesenchymal transition (EMT) involves complex transcriptional reprogramming and has been closely linked to malignant progression. Although various epigenetic modifications, such as histone deacetylation and H3K9 methylation, have been implicated in this process, how they are coordinated remains elusive. We recently revealed that MPP8 couples H3K9 methylation and DNA methylation for E-cadherin gene silencing and promotes tumor cell migration, invasion, and EMT. Here, we show that MPP8 cooperates with the class III HDAC SIRT1 in this process through their physical interaction. SIRT1 antagonizes PCAF-catalyzed MPP8-K439 acetylation to protect MPP8 from ubiquitin-proteasome-mediated proteolysis. Conversely, MPP8 recruits SIRT1 for H4K16 deacetylation after binding to methyl-H3K9 on target promoters. Consequently, disabling either MPP8 methyl-H3K9 binding or SIRT1 interaction de-represses E-cadherin and reduces EMT phenotypes, as does knockdown of MPP8 or SIRT1 in prostate cancer cells. These results illustrate how SIRT1 and MPP8 reciprocally promote each other's function and coordinate epithelial gene silencing and EMT.
作为一个关键的发育过程，上皮-间质转化（EMT）涉及复杂的转录重编程，并且与恶性进展密切相关。尽管各种表观遗传修饰，如组蛋白去乙酰化和H3K9甲基化，都与这一过程有关，但它们是如何协调的仍不清楚。我们最近发现，MPP8将H3K9甲基化和DNA甲基化偶联起来以沉默E-钙黏蛋白基因，并促进肿瘤细胞的迁移、侵袭和EMT。在这里，我们表明MPP8在这个过程中通过与III类组蛋白去乙酰化酶SIRT1的物理相互作用而与之合作。SIRT1拮抗PCAF催化的MPP8-K439乙酰化，以保护MPP8免受泛素-蛋白酶体介导的蛋白水解。相反，MPP8在与靶启动子上的甲基-H3K9结合后招募SIRT1进行H4K16去乙酰化。因此，破坏MPP8与甲基-H3K9的结合或SIRT1的相互作用会解除对E-钙黏蛋白的抑制并减少EMT表型，前列腺癌细胞中MPP8或SIRT1的敲低也是如此。这些结果说明了SIRT1和MPP8如何相互促进彼此的功能，并协调上皮基因沉默和EMT。
