Knockdown of ubiquitin-conjugating enzyme E2T (UBE2T) suppresses lung adenocarcinoma progression via targeting fibulin-5 (FBLN5)

Abstract

Lung adenocarcinoma (LUAD) is the main histological type of lung cancer, which is the leading cause of cancer-related deaths. Accumulating evidence has displayed that UBE2T is related to tumor progression. However, its role in LUAD has not been fully elucidated. The expression of UBE2T was detected in LUAD tissues by qRT-PCR, western blotting, and immunohistochemistry. UBE2T shRNAs were transfected into LUAD cells to analyze the consequent alteration in function through CCK-8 assay, Edu assay, transwell assay, and TUNEL staining. The potential mechanism of UBE2T was analyzed through GEPIA and verified using ChIP, EMSA, and GST pull-down assays. Furthermore, a xenograft mouse model was used to assess UBE2T function in vivo . Results showed that UBE2T level was significantly elevated in LUAD tissues and high UBE2T expression was associated with poor overall survival and disease-free survival. Results from the loss-of-function experiments in vitro showed that UBE2T modulated LUAD cell proliferation, migration, invasion, and apoptosis. The mechanism analysis demonstrated that silence of UBE2T increased FBLN5 expression and inhibited the activation of p-ERK, p-GSK3β, and β-catenin. Moreover, following knockdown of UBE2T, the cell proliferation, migration, and invasion were decreased, and sh-FBLN5 partially reverse the decrease. In in vivo experiments, it was found that UBE2T knockdown inhibits the tumor growth in LUAD. Immunohistochemically, there was a reduction in Ki67 and an increase in FBLN5 in UBE2T shRNA-treated tumor tissues. In conclusion, UBE2T might be a potential biomarker of LUAD, and targeting the UBE2T/FBLN5 axis might be a novel treatment strategy for LUAD.

LINC01089 blocks malignant progression of thyroid cancer by binding miR-27b-3p to enhance the FBLN5 protein level

“…In addition, FBLN5 expression was reduced by miR-27b-3p overexpression, suggesting that FBLN5 is the downstream target gene of LINC00987 in thyroid cancer. FBLN5 expression was decreased in lung adenocarcinoma, cervical cancer, and prostate cancer [ 21 , 31 , 32 ]. FBLN5 overexpression reduces tumor angiogenesis, suppresses lung adenocarcinoma and ovarian cancer progression, and has anti-tumor function [ 21 , 33 , 34 ].…”

“…FBLN5 expression was decreased in lung adenocarcinoma, cervical cancer, and prostate cancer [ 21 , 31 , 32 ]. FBLN5 overexpression reduces tumor angiogenesis, suppresses lung adenocarcinoma and ovarian cancer progression, and has anti-tumor function [ 21 , 33 , 34 ]. In addition, FBLN5 acted as a target gene that can be regulated by miRNAs, such as miR-552/370/27a-3pp, thereby exerting the function of an anti-oncogene in NSCLC, breast cancer, and ovarian carcinoma [ 22 , 35 , 36 ].…”

Diverse roles of UBE2T in cancer (Review)

“…Knockdown of UBE2T decreased the mono-ubiquitination of FANCD2, while overexpression of UBE2T increased it (77). Cell proliferation, migration and invasion abilities decreased after knocking down of UBE2T, while silencing UBE2T increased fibulin 5, and inhibited the activation of phosphorylated (p)-ERK, p-GSK3β and β-catenin (78).…”

Identification of small‐molecule binding sites of a ubiquitin‐conjugating enzyme‐UBE2T through fragment‐based screening

“…It is critical for the initiation and progression of pancreatic cancer (Zheng et al, 2020) and has been demonstrated to promote the proliferation of renal cell carcinoma cells through regulating phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) signaling (Hao et al, 2019). Suppression of UBE2T activity has also exhibited an inhibitory effect on the proliferation and invasion of ovarian cancer cells (Cui et al, 2022), lung adenocarcinoma (Li et al, 2022), and other cancers (Liu et al, 2017). Finally, UBE2T also plays important roles in primary cellular processes and participates in protein–protein interactions (Hodson et al, 2014; Lim et al, 2016; Longerich et al, 2014).…”