Li Jing, Li Ya, Xu Feng, Sun Binghua, Yang Lei, Wang Huanan
Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China.
Department of Gastroenterology Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China.
Exp Cell Res. 2022 Jun 15;415(2):113148. doi: 10.1016/j.yexcr.2022.113148. Epub 2022 Apr 9.
Previous studies have demonstrated that the aberrant expression of deubiquitinating enzymes (DUBs) is closely associated with cancer progression, including gastric cancer (GC), due to its role in maintaining protein stability. The 26S proteasome non-ATPase regulatory subunit 14 (PSMD14), a member of the DUBs family, is reported to be highly expressed in some types of cancer and its overexpression indicates poor prognosis, but the function of PSMD14 in GC remains unclear. To investigate this issue, we first analyzed the PSMD14 expression via the TNMplot database and found that PSMD14 was up-regulated in GC tissues compared with the adjacent normal tissues (P < 0.01). PSMD14 knockdown notably inhibited cell proliferation, migration, and invasion in vitro, which was confirmed through in vivo experiments. However, PSMD14 overexpression presented the opposite effects. Additionally, we found that PSMD14 deletion inhibited the protein level of polypyrimidine tract-binding protein 1 (PTBP1), an activator of GC development. Further investigation confirmed that PSMD14 and PTBP1 presented co-localization and had an endogenous interaction. PSMD14 was revealed to promote the deubiquitination and stabilization of PTBP1, and PTBP1 knockdown reversed the effects caused by PSMD14 overexpression on cell function. Collectively, we demonstrate that PSMD14 as a deubiquitinating enzyme may promote the development of GC via stabilizing PTBP1, which provides a theoretical basis for a therapeutic target against GC.
先前的研究表明，去泛素化酶（DUBs）的异常表达与癌症进展密切相关，包括胃癌（GC），因为其在维持蛋白质稳定性方面发挥作用。26S蛋白酶体非ATP酶调节亚基14（PSMD14）是DUBs家族的成员，据报道在某些类型的癌症中高度表达，其过表达表明预后不良，但PSMD14在GC中的功能仍不清楚。为了研究这个问题，我们首先通过TNMplot数据库分析了PSMD14的表达，发现与相邻正常组织相比，PSMD14在GC组织中上调（P < 0.01）。PSMD14敲低显著抑制体外细胞增殖、迁移和侵袭，这在体内实验中得到证实。然而，PSMD14过表达呈现相反的效果。此外，我们发现PSMD14缺失抑制了多嘧啶序列结合蛋白1（PTBP1）的蛋白水平，PTBP1是GC发展的激活因子。进一步研究证实PSMD14和PTBP1呈现共定位并具有内源性相互作用。结果显示PSMD14促进PTBP1的去泛素化和稳定，并且PTBP1敲低逆转了PSMD14过表达对细胞功能的影响。总体而言，我们证明PSMD14作为一种去泛素化酶可能通过稳定PTBP1促进GC的发展，这为针对GC的治疗靶点提供了理论基础。
