Ji Liu

The deubiquitinase YOD1 suppresses tumor progression by stabilizing ZNF24 in clear cell renal carcinoma

Abstract Metastasis remains a significant challenge in the management of clear cell renal cell carcinoma (ccRCC), and a continued focus on its underlying mechanisms is crucial for improving patient outcomes and optimizing clinical therapies. The ovarian-tumor related protease (OTU) is involved in regulating critical cell signaling pathways, but the functions of most OTUs have yet to be explored. In this study, an unbiased RNAi screening revealed that ovarian tumor domain-containing 2 (YOD1) knockdown significantly promoted cell metastasis. YOD1 downregulation promoted ccRCC growth and metastasis both in vitro and in vivo. Notably, YOD1 knockdown stimulated the growth of organoids derived from ccRCC patients. Further investigation revealed that YOD1 directly interacted with and stabilized Zinc finger protein 24 (ZNF24) expression by deubiquitination in a manner dependent on its catalytic activity. YOD1 inhibition attenuated ZNF24 transcriptional repression of vascular endothelial growth factor A (VEGFA), thereby promoting VEGFA gene expression. Furthermore, ZNF24 was identified as a key mediator of YOD1 function. The expression of YOD1 and ZNF24 was significantly downregulated in tumor tissues, with a strong correlation between them. Importantly, reduced YOD1 and ZNF24 levels were strongly associated with poor clinical outcomes in ccRCC patients. Our results reveal the mechanism by which YOD1 regulates VEGFA transcription and suppresses tumorigenesis by deubiquitinating ZNF24, providing a therapeutic target in ccRCC.

METTL16 Inhibits the Malignant Progression of Epithelial Ovarian Cancer through the lncRNA MALAT1/β‐Catenin Axis

Epithelial ovarian cancer (EOC) ranks third in the incidence of gynecological malignancies. m6A methylation as RNA modification plays a crucial role in the evolution, migration, and invasion of various tumors. However, the role of m6A methylation in ovarian cancer (OC) only recently has begun to be appreciated. Therefore, we used various bioinformatic methods to screen the public GEO datasets of epithelial ovarian cancer (EOC) for m6A methylation‐related regulators. We identified methyltransferase 16 (METTL16) that was dramatically downregulated in EOC as such a regulator. We also identified metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1), a known target lncRNA of METTL16, in these five GEO datasets. RT‐qPCR and immunohistochemical staining confirmed that compared with the normal ovarian tissues and cells, METTL16 was significantly downregulated, while lncRNA MALAT1 was significantly upregulated, in 30 EOC tissues of our own validation cohorts and EOC cell lines, revealing a negative correlation between METTL16 and lncRNA MALAT1. Moreover, our analysis unveiled a correlation between downregulated METTL16 and the known adverse prognostic factors of EOC patients in our own cohorts. The CCK‐8, EdU, scratch wound healing, and transwell invasion assays revealed that METTL16 significantly suppressed the proliferating, migrating, and invading abilities of OC cells. The inhibitory effects of METTL16 on the in vivo tumor growth of EOC cells were measured by subcutaneous tumor formation assay in mice. Furthermore, the RIP, RNA stability assay, western blotting, and cytoimmunofluorescence staining showed that METTL16 hindered the growth of EOC cells through promoting the degradation of MALAT1 by binding that, in turn, upregulates β‐catenin protein and promotes nuclear transport of β‐catenin protein in EOC cells. This study suggests that METTL16 acts as a tumor suppressor gene of EOC by achieving its inhibitory function on the malignant progression of EOC through the METTL16/MALAT1/β‐catenin axis that are new targets for EOC diagnosis and therapy.