Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou 310058, China.
The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310018, China.
Proc Natl Acad Sci U S A. 2024 Oct 29;121(44):e2407904121. doi: 10.1073/pnas.2407904121. Epub 2024 Oct 21.
The dysfunction of the ubiquitin-proteasome system (UPS) facilitates the malignant progression of hepatocellular carcinoma (HCC). While targeting the UPS for HCC therapy has been proposed, identifying effective targets has been challenging. In this study, we conducted a focused screen of siRNA libraries targeting UPS-related WD40 repeat (WDR) proteins and found that silencing WDR20, a deubiquitinating enzyme activating factor, selectively inhibited the proliferation of HCC cells without affecting normal hepatocytes. Moreover, the downregulation of WDR20 expression induced HCC cellular senescence and suppressed tumor progression in xenograft, sleeping beauty transposon/transposase, and hydrodynamic tail vein injection-induced HCC models, and / HCC transgenic mouse models. Mechanistically, we found that WDR20 silencing disturbed the protein stability of c-Myc, orchestrating the simultaneous USP12/46-mediated deubiquitination of c-Myc, thereby promoting the transcriptional activation of . Further investigation revealed a positive coexpression of WDR20 and c-Myc in a tissue microarray with 88 HCC clinical samples. By employing three patient-derived organoids from individuals with HCC, we have validated the decrease in c-Myc expression and the significant induction of senescence and growth inhibition following silencing of WDR20. This study not only uncovers the biological function of WDR20 and elucidates the molecular mechanism underlying its negative regulation of HCC cellular senescence but also highlight the potential of WDR20 as a promising target for HCC therapy.
泛素-蛋白酶体系统（UPS）的功能障碍促进了肝细胞癌（HCC）的恶性进展。虽然已经提出了针对 HCC 治疗的 UPS 靶向治疗，但确定有效的靶点一直具有挑战性。在这项研究中，我们对针对 UPS 相关 WD40 重复（WDR）蛋白的 siRNA 文库进行了重点筛选，发现沉默去泛素化酶激活因子 WDR20 选择性地抑制 HCC 细胞的增殖，而不影响正常肝细胞。此外，下调 WDR20 表达诱导 HCC 细胞衰老，并抑制异种移植、睡美人转座子/转座酶和水力尾静脉注射诱导的 HCC 模型以及 HCC 转基因小鼠模型中的肿瘤进展。在机制上，我们发现 WDR20 沉默扰乱了 c-Myc 的蛋白质稳定性，协调了 USP12/46 对 c-Myc 的同时去泛素化，从而促进了 的转录激活。进一步的研究在包含 88 个 HCC 临床样本的组织微阵列中发现了 WDR20 和 c-Myc 的阳性共表达。通过使用来自 HCC 个体的三个患者来源的类器官，我们验证了 WDR20 沉默后 c-Myc 表达的降低以及衰老和生长抑制的显著诱导。这项研究不仅揭示了 WDR20 的生物学功能，并阐明了其对 HCC 细胞衰老的负调控的分子机制，还突出了 WDR20 作为 HCC 治疗有前途的靶点的潜力。
