RNF115 promotes lung adenocarcinoma through Wnt/β-catenin pathway activation by mediating APC ubiquitination

Abstract

Background Patients with lung adenocarcinoma (LUAD) have high mortality rate and poor prognosis. The LUAD cells display increased aerobic glycolysis, which generates energy required for their survival and proliferation. Deregulation of Wnt/β-catenin signaling pathway induces the metabolism switching and oncogenesis in tumor cells. RING finger protein 115 (RNF115) is an E3 ligase for ubiquitin-mediated degradation. Although the oncogenic functions of RNF115 have been revealed in breast tumor cells, the effect of RNF115 on lung cancer is still not clear. Methods RNF115 expression and its correlation with the features of LUAD patients were analyzed by using public database and our own cohort. The functions of RNF115 in proliferation and energy metabolism in LUAD cells were explored by downregulating or upregulating RNF115 expression. Results We demonstrated that RNF115 was overexpressed in LUAD tissues and its expression was positively correlated with the poor overall survival of LUAD patients. Moreover, RNF115 overexpression inhibited LUAD cell apoptosis and promoted cellular proliferation and metabolism in LUAD cells. On the contrary, RNF115 knockdown displayed reverse effects. Furthermore, the underlying mechanism of the biological function of RNF115 in LUAD was through regulating Wnt/β-catenin pathway via ubiquitination of adenomatous polyposis coli (APC). Conclusion The current study reveals a close association between RNF115 expression and prognostic conditions in LUAD patients and the oncogenic roles of RNF115 in LUAD at the first time. These findings may help establish the foundation for the development of therapeutics strategies and clinical management for lung cancer in future.

The Systematic Analyses of RING Finger Gene Signature for Predicting the Prognosis of Patients with Hepatocellular Carcinoma

“…TRIM25 takes part in tumor growth, metastasis, and chemoresistance with its ubiquitin ligase activities [ 18 , 44 ]. RNF115 is correlated with the prognosis of patients with lung adenocarcinoma or invasive breast cancer [ 45 , 46 ]. As a master regulator of DNA repair, dysfunction of TRAIP is associated with tumor development and progression [ 47 , 48 ].…”

Multifaceted Roles of the E3 Ubiquitin Ligase RING Finger Protein 115 in Immunity and Diseases

“…The RAB proteins are small GTPases that play essential roles in intracellular vesicle trafficking (55)(56)(57). Specifically, RAB7 is involved in late endocytic traffic and lysosome acidification as well as (41,42) Lung cancer inhibition cancer cell growth induction ubiquitination and degradation of cMyc (43) Gastric cancer promotation cancer cell growth interaction and stablization SNX7 to promote autophagosome maturation (52) mitochondria-lysosome contact (38). It is observed that overexpression of RNF115 promotes the late endosomelysosome fusion and acidification and the trafficking of HIV-1 viral particles to the lysosomes for degradation (15,39,44), whereas knockdown of RNF115 leads to the retention of EGFR in the late endocytic compartments and hyper-phosphorylation and stabilization of EGFR (27).…”

“…The reason behind the discrepancies is unclear. However, it has been shown that RNF115 promotes lung adenocarcinoma by targeting p53, APC and c-Myc for ubiquitination and degradation, indicating complicated roles of RNF115 in lung cancer (41)(42)(43). RNF115 is expressed in all renal oncocytoma cases and in cases designated as oncocytic neoplasm which favor oncocytoma but barely expressed in renal cell carcinoma (60).…”

“…In lung adenocarcinoma cell lines, RNF115 has been shown to catalyze the ubiquitination of p53 and knockdown of RNF115 significantly inhibits the cell viability in vitro by inducing G1 phase arrest and tumor growth in a xenograft model ( 41 ). Moreover, RNF115 overexpression promotes ubiquitination of adenomatous polyposis coli (APC) to modulate the Wnt/β-catenin pathway activation, and thereby promotes the proliferation and inhibits the apoptosis of lung adenocarcinoma cell lines ( 42 ). In contrast, however, another study has reported that RNF115 induces ubiquitination and degradation of c-Myc and thereby inhibits H1299 lung cancer cell growth ( 43 ).…”

Wnt signaling pathway-derived score for predicting therapeutic resistance and tumor microenvironment in lung adenocarcinoma

“…Wnt signal abnormalities are associated with some tumor disease, and the most significant ones are lung cancer, breast cancer, bladder cancer, clear cell renal cell cancer and prostate cancer ( Xu et al, 2022 ; Xue et al, 2022 ; Zhao et al, 2022 ). Most investigation on Wnt signaling pathway in lung adenocarcinoma only focus on Wnt pathway as a downstream signaling pathway to regulate the proliferation and differentiation of lung adenocarcinoma cells ( Tammela et al, 2017 ; Wu et al, 2021 ).…”