Kim Jongchan, Alavi Naini Fatemeh, Sun Yutong, Ma Li
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030, USA.
Houston Baptist University Houston, Texas 77074, USA.
Am J Cancer Res. 2018 Sep 1;8(9):1823-1836. eCollection 2018.
β-catenin is not only a key component of adherens junctions but also a transcriptional co-activator downstream of canonical Wnt signaling. The Wnt/β-catenin pathway plays critical roles in animal development and tissue homeostasis, while mutation or overexpression of β-catenin often leads to tumorigenesis and metastasis. Ubiquitination-mediated proteasomal degradation of β-catenin is a key molecular event in the Wnt/β-catenin pathway. Because deubiquitination of β-catenin can stabilize β-catenin and activate Wnt/β-catenin signaling, targeting the β-catenin deubiquitinase may provide a strategy for treating β-catenin-driven cancers. Here, by screening a human deubiquitinase library, we identified USP2a as a deubiquitinase that binds, deubiquitinates, and stabilizes β-catenin protein. USP2a promotes the nuclear accumulation and transcriptional activity of β-catenin, leading to elevated expression of Wnt/β-catenin target genes. Importantly, either genetic knockdown or pharmacological inhibition of USP2a leads to β-catenin destabilization. These findings suggest that USP2a may serve as a therapeutic target for targeting the cancer-promoting protein β-catenin.
β-连环蛋白不仅是黏附连接的关键组成部分，也是经典Wnt信号下游的转录共激活因子。Wnt/β-连环蛋白通路在动物发育和组织稳态中发挥着关键作用，而β-连环蛋白的突变或过表达通常会导致肿瘤发生和转移。泛素化介导的β-连环蛋白蛋白酶体降解是Wnt/β-连环蛋白通路中的关键分子事件。由于β-连环蛋白的去泛素化可以稳定β-连环蛋白并激活Wnt/β-连环蛋白信号，靶向β-连环蛋白去泛素酶可能为治疗β-连环蛋白驱动的癌症提供一种策略。在此，通过筛选人类去泛素酶文库，我们鉴定出USP2a是一种与β-连环蛋白结合、使其去泛素化并稳定β-连环蛋白蛋白的去泛素酶。USP2a促进β-连环蛋白的核积累和转录活性，导致Wnt/β-连环蛋白靶基因的表达升高。重要的是，基因敲低或药理学抑制USP2a都会导致β-连环蛋白不稳定。这些发现表明，USP2a可能作为靶向促癌蛋白β-连环蛋白的治疗靶点。
