Zhan Wei, Liao Xin, Liu Jing, Tian Tian, Yu Lei, Li Rui
Department of Colorectal Surgery, Affiliated Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, China.
Department of Imaging, Affiliated Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, China.
Oncogenesis. 2020 May 13;9(5):48. doi: 10.1038/s41389-020-0234-z.
Histone modification represents a crucial level of gene expression regulation and is actively involved in the carcinogenesis of human colorectal cancer. Histone acetyltransferases and deacetylases modulate the landscape of histone acetylation, which controls key genes of colorectal cancer pathology. However, the fine tune of histone deacetylases, especially the modification of histone deacetylases that facilitate colorectal cancer, remains elusive. Here, we identified that an ubiquitin-specific protease (USP), USP38, was downregulated in clinical colorectal cancer samples and colorectal cancer cell lines. Importantly, our results showed that USP38 was a specific deubiquitinase of histone deacetylase 3 (HDAC3), which cleaved the lysine 63 ubiquitin chain. Ubiquitination of HDAC3 resulted in a decreased level of histone acetylation and finally led to upregulation of cancer stem cell-related genes. In addition, our results demonstrated a tumor suppressor role of USP38 in colorectal cancer via inhibiting cancer stem cell populations. Most importantly, the ubiquitination level of HDAC3 was responsible for USP38 mediated regulation of cancer stem cell-related transcripts. Our data provided functional insights of USP38 and HDAC3 in colorectal cancer and revealed novel mechanisms of ubiquitination mediated epigenetic regulation.
组蛋白修饰是基因表达调控的关键层面，且积极参与人类结直肠癌的致癌过程。组蛋白乙酰转移酶和去乙酰化酶调节组蛋白乙酰化格局，而这控制着结直肠癌病理学的关键基因。然而，组蛋白去乙酰化酶的精细调节，尤其是促进结直肠癌的组蛋白去乙酰化酶的修饰，仍然难以捉摸。在此，我们发现一种泛素特异性蛋白酶（USP），即USP38，在临床结直肠癌样本和结直肠癌细胞系中表达下调。重要的是，我们的结果表明USP38是组蛋白去乙酰化酶3（HDAC3）的特异性去泛素化酶，它能切割赖氨酸63位的泛素链。HDAC3的泛素化导致组蛋白乙酰化水平降低，最终导致癌症干细胞相关基因上调。此外，我们的结果证明USP38通过抑制癌症干细胞群体在结直肠癌中发挥肿瘤抑制作用。最重要的是，HDAC3的泛素化水平负责USP38介导的对癌症干细胞相关转录本的调控。我们的数据提供了USP38和HDAC3在结直肠癌中的功能见解，并揭示了泛素化介导的表观遗传调控的新机制。
