Ubiquitin C-Terminal Hydrolase L5 (UCHL5) Accelerates the Growth of Endometrial Cancer via Activating the Wnt/β-Catenin Signaling Pathway

Abstract

Endometrial cancer (EC) is the most prevalent gynecological malignancy with high mortality. Chemotherapy plays a pivotal role both in an adjuvant setting and in exclusive treatment. However, current pharmacotherapies are limited and not ideal for improving the overall survival of EC patients. Thus, identification of the underlying molecular mechanisms responsible for initiation and progression of EC is imperative for developing novel therapeutic strategies. Ubiquitin C-terminal hydrolase L5 (UCHL5) has been found to aggravate tumor growth and metastasis in several different types of tumor models such as esophageal squamous cell carcinoma, hepatocellular carcinoma, and epithelial ovarian cancer. However, whether UCHL5 influences the growth of EC has not been elucidated. To expose the role of UCHL5 on EC, bioinformatics analysis was conducted, and it hinted that UCHL5 was overexpressed in EC tissues and associated with lower overall survival. Consistently, the overexpression of UCHL5 in EC tissues and cell lines was further confirmed by western blot (WB) and polymerase chain reaction (PCR) compared with non-tumor control. Lentivirus vectors carrying UCHL5 shRNA or CD sequences were used to reduce or overexpress the UCHL5 gene, respectively. Cell proliferation and cycle were facilitated, and cell apoptosis was decreased when the UCHL5 gene was overexpressed in EC cell lines. These results were opposite in UCHL5 knockdown EC cells. Additionally, the expression of β-catenin is positively related to UCHL5 levels and the tumorigenic effects of UCHL5 overexpression were reversed by the Wnt/β-catenin pathway inhibitor XAV939. Thus, Wnt/β-catenin pathway activation may be a partial mechanism responsible for the promoting effects of UCHL5 on EC growth. In conclusion, UCHL5 accelerated the growth of EC via the Wnt/β-catenin pathway and was expected to be an attractive target for EC treatment.

Targeting Ubiquitin–Proteasome System With Copper Complexes for Cancer Therapy

“…Accumulating evidence suggests a protumor role of proteasomal DUBs in different cancers. For example, UCHL5 accelerates growth of endometrial cancer by activating the WNT-catenin beta 1 (CTNNB1) pathway ( Liu et al, 2020 ). UCHL5 positively regulates Hedgehog signaling by removing ubiquitination of Smoothened, Frizzled class receptor (SMO) protein in cancer cells ( Zhou et al, 2018 ).…”

Circ_0109046 promotes the malignancy of endometrial carcinoma cells through the microRNA‐105/SOX9/Wnt/β‐catenin axis

“…48,49 This signaling is one of the most frequent signaling pathway implicated in human cancer progression including EC. [50][51][52][53] In addition, the Wnt pathway has been reported to be involved with estrogen and progesterone and implicated in the activation of other important pathways such as mTOR and Hedgehog, which also indicated its therapeutic potential in the management of gynecologic cancers including EC. 54 To validate if there is a SOX9-Wnt/β-catenin crosstalk in EC as well, we determined the activity of this pathway in cells.…”

“…In the presence of Wnt ligands, β‐catenin is isolated from the destruction complex and accumulates in cytoplasm, which further translocate into the nuclear where it can interact with the T cell factor/Lymphoid Enhancer Factor transcription factors and promotes the downstream targets including c‐Myc and cyclin D1, and matrix metalloproteinase 1 48,49 . This signaling is one of the most frequent signaling pathway implicated in human cancer progression including EC 50–53 . In addition, the Wnt pathway has been reported to be involved with estrogen and progesterone and implicated in the activation of other important pathways such as mTOR and Hedgehog, which also indicated its therapeutic potential in the management of gynecologic cancers including EC 54 .…”

Ubiquitin–proteasome system (UPS) as a target for anticancer treatment

“…In endometrial cancer (EC), Wnt signaling is involved in cell survival, cell cycle, proliferation and metastasis. UCH37 activates Wnt signaling and affects the expression of its target genes, such as β-catenin, cyclin D1 and c-Myc, thereby increasing the cell growth of EC (Liu et al 2020 ). It also regulates TGF-β signaling, and aberrant TGF-β signaling is closely related to the development of cancer.…”