USP22调控NF-κB-Wnt信号通路促进大肠癌的转移

We revealed that cancer cells manifesting USP22, one subunit of SAGA member, showed a strong tendency to metastasis; the high expression of USP22 was accompanied by the high expression of NF-κB and β-catenin. The previous researches showed NF-κB enhanced β-catenin activation and thus acquired tumor-metastasizing capacity; SAGA promoted the transcription activity of NF-κB; histone ubiquitination regulatedβ-catenin function; and USP22 can deubiquitinate H2Bub to activate the transcriptional program. Thus, we proposed that USP22 promoted colorectal cancer (CRC) metastasis via modulating NF-κB–Wnt signaling pathway. The detailed mechanism was described in the following procedure: USP22 activated RelA/p50 by the recruitment of hSAGA, integrated the complex with Tcf/β-catenin via CBP, and regulated the deubiquitination activity to activate the β-catenin-dependent target genes by trans-histone crosstalk mechanism. To test this hypothesis, from molecular, cell and tissue etc., we sought to explore the mechanism of USP22 activating NF-κB–Wnt signaling pathway, and elucidate the pivotal role of histone ubiquitin modification. The current study will provide the new viewpoint of epigenetic modifications to reveal the mechanism of CRC, and facilitate theory expansion about the targeted therapy for CRC metastasis.

我们证实SAGA成员USP22标记的癌细胞表现为强烈的转移倾向，且USP22高表达时，NF-κB和β-catenin升高。鉴于NF-κB可活化β-catenin赋予癌细胞转移能力；SAGA促进NF-κB的转录活性，组蛋白泛素化修饰调控β-catenin的功能区，而USP22通过H2B去泛素化激活转录。故我们提出USP22通过活化NF-κB-Wnt通路促进大肠癌的转移，即：USP22募集SAGA活化RelA/p50，促使RelA/p50/CBP/Tcf/β-catenin复合体形成，通过USP22去泛素化作用，以组蛋白交互应答的形式启动β-catenin控制的靶基因转录。为此，我们从分子、细胞及组织等方面探讨USP22活化NF-κB-Wnt信号通路的机制，明确组蛋白泛素修饰的核心调控作用。本研究将从表观修饰的新视点为揭示大肠癌转移的机制奠定基础，为临床实现对大肠癌转移的有效干预提供新的思路。

在前期工作中证实USP22标记的癌细胞表现为强烈的转移倾向。结合前期工作，我们提出USP22通过活化NF-κB-Wnt通路促进大肠癌转移的机制。在通过本项国自然基金的资助，我们从分子、细胞及组织等方面完成了以下工作：1）证实USP22可作为大肠癌干细胞标记物，通过活化Wnt/β-catenin通路维持肿瘤干细胞特性，促使大肠癌的复发及耐药；2）阐明USP22通过调控AP4诱导上皮-间充质转化，增强大肠癌的转移能力；3）说明了与USP22相关联的CRNDE基因可能是通过调节miR-181a-5p表达调控Wnt/β-catenin信号通路来调控CRC进展及耐药性；4）从表观遗传学的角度，阐述了8个lncRNAs的表达参与大肠癌的进展，可将患者的预后进行分层；5）阐述了MAL2和TPD52可作为大肠癌的预后靶标，其机制可能为诱导EMT、活化FAK介导的整合素通路和PI3K/Akt信号导致的。该课题阐明了USP22是种肿瘤干细胞标记物，与大肠癌的转移、复发及耐药密切相关，为临床实现对大肠癌转移的有效干预提供新的思路。