RESUMO
S-palmitoylation is a reversible protein lipidation that controls the subcellular localization and function of targeted proteins, including oncogenes such as N-RAS. The depalmitoylation enzyme family ABHD17s can remove the S-palmitoylation from N-RAS to facilitate cancer development. We previously showed that ABHD17C has oncogenic roles in hepatocellular carcinoma (HCC) cells, and its mRNA stability is controlled by miR-145-5p. However, it is still unclear whether ABHD17C is regulated at the post-translational level. In the present study, we identified multiple ubiquitin-specific proteases (USPs) that can stabilize ABHD17C by inhibiting the ubiquitin-proteasome-mediated degradation. Among them, USP35 is the most potent stabilizer of ABHD17C. We found a positive correlation between the elevated expression levels of USP35 and ABHD17C, together with their association with increased PI3K/AKT pathway activity in HCCs. USP35 knockdown caused decreased ABHD17C protein level, impaired PI3K/AKT pathway, reduced proliferation, cell cycle arrest, increased apoptosis, and mitigated migration and invasion. USP35 can interact with and stabilize ABHD17C by inhibiting its ubiquitination. Overexpression of ABHD17C can rescue the defects caused by USP35 knockdown in HCC cells. In support of these in vitro observations, xenograft assay data also showed that USP35 deficiency repressed HCC development in vivo, characterized by reduced proliferation and disrupted PI3K/AKT signaling. Together, these findings demonstrate that USP35 may promote HCC development by stabilization of ABHD17C and activation of the PI3K/AKT pathway.
RESUMO
Cancer is a grave and persistent illness, with the rates of both its occurrence and death toll increasing at an alarming pace. N6-methyladenosine (m6A), the most prevalent mRNA modification in eukaryotic organisms, is catalyzed by methyltransferases and has a significant impact on various aspects of cancer progression. WT1-associated protein (WTAP) is a crucial component of the m6A methyltransferase complex, catalyzing m6A methylation on RNA. It has been demonstrated to participate in numerous cellular pathophysiological processes, including X chromosome inactivation, cell proliferation, cell cycle regulation, and alternative splicing. A better understanding of the role of WTAP in cancer may render it a reliable factor for early diagnosis and prognosis, as well as a key therapeutic target for cancer treatment. It has been found that WTAP is closely related to tumor cell cycle regulation, metabolic regulation, autophagy, tumor immunity, ferroptosis, epithelial mesenchymal transformation (EMT), and drug resistance. In this review, we will focus on the latest advances in the biological functions of WTAP in cancer, and explore the prospects of its application in clinical diagnosis and therapy.
RESUMO
Background: Wilms tumor 1-associated protein (WTAP) plays a critical role in ribonucleic acid (RNA) methylation of N6 adenosine (m6A) modification, which is closely related with varieties of biological process. However, the role of WTAP in cancers remains to be determined. This study is designed to demonstrate the prognostic landscape of WTAP in pan-cancer and explore the relationship between WTAP expression and immune infiltration. Methods: Here, we investigated the expression level and prognostic role of WTAP in pan-cancer using multiple databases, including PrognoScan, GEPIA, and Kaplan-Meier Plotter. Then, applying the GEPIA and TIMER databases, we illustrated the correlations between WTAP expression and immune infiltration in tumors, especially liver hepatocellular carcinoma (LIHC), and esophageal carcinoma (ESCA). Results: WTAP had significant higher expression levels in tumor tissues of ESCA, LIHC, etc., while lower expression levels in those of bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), etc. And WTAP demonstrated multifaceted prognostic value in cancers. Of our interests, WTAP exerted a harmful effect on LIHC patient for overall survival (OS) and progression free survival (PFS). WTAP expression also significantly associated with the infiltration levels of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells (DC) in LIHC but not ESCA. Furthermore, combined analysis about WTAP expression level and immune cell specific gene markers implied WTAP correlates with regulatory cells (T reg) infiltration in LIHC and ESCA. Conclusion: The m6A regulator WTAP can serve as a prognostic biomarker for certain tumor types in pan-cancer and potentially result from immune cell infiltration.