Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
Cell Res. 2018 Sep;28(9):934-951. doi: 10.1038/s41422-018-0079-6. Epub 2018 Aug 22.
Hyperactivation of EGFR/PI3K/AKT is a prominent feature of various human cancers. Thus, understanding how this molecular cascade is balanced is of great importance. We report here that the ubiquitin-specific protease USP43 is physically associated with the chromatin remodeling NuRD complex and catalyzes H2BK120 deubiquitination. Functionally this coordinates the NuRD complex to repress a cohort of genes, including EGFR, which are critically involved in cell proliferation and carcinogenesis. We show that USP43 strongly suppresses the growth and metastasis of breast cancer in vivo. Interestingly, USP43 also exists in the cytoplasm, where it is phosphorylated by AKT, enabling its binding to the 14-3-3β/ε heterodimer and sequestration in the cytoplasm. Significantly, hyperactivation of EGFR/PI3K/AKT in breast cancer is associated with the cytoplasmic retention of USP43 and thus, the inhibition of its transcriptional regulatory function. Moreover, cancer-associated mutations of USP43 affect its subcellular localization and/or epigenetic regulatory functions. Nuclear USP43 is significantly reduced in breast carcinomas and is associated with EGFR accumulation and AKT hyperactivation. A low level of nuclear USP43 correlates with higher histologic grades and poor prognosis. Our study identifies USP43 to be an H2BK120 deubiquitinase and a potential tumor suppressor and reveals a reciprocally inhibitory loop between USP43 and EGFR/PI3K/AKT, whose imbalance drives breast carcinogenesis.
EGFR/PI3K/AKT 的过度激活是多种人类癌症的显著特征。因此，了解这种分子级联反应是如何平衡的具有重要意义。我们在这里报告称，泛素特异性蛋白酶 USP43 与染色质重塑 NuRD 复合物物理结合，并催化 H2BK120 的去泛素化。从功能上讲，这协调了 NuRD 复合物来抑制一组基因，包括 EGFR，这些基因在细胞增殖和癌变中起着至关重要的作用。我们表明，USP43 强烈抑制体内乳腺癌的生长和转移。有趣的是，USP43 也存在于细胞质中，在细胞质中它被 AKT 磷酸化，使其能够与 14-3-3β/ε 异二聚体结合并被隔离在细胞质中。重要的是，乳腺癌中 EGFR/PI3K/AKT 的过度激活与 USP43 的细胞质保留有关，从而抑制其转录调节功能。此外，USP43 的癌症相关突变会影响其亚细胞定位和/或表观遗传调节功能。USP43 在乳腺癌中的核表达显著减少，与 EGFR 积累和 AKT 过度激活有关。核 USP43 水平低与组织学分级较高和预后不良相关。我们的研究将 USP43 鉴定为 H2BK120 去泛素酶和潜在的肿瘤抑制因子，并揭示了 USP43 和 EGFR/PI3K/AKT 之间的相互抑制循环，其失衡驱动了乳腺癌的发生。
