REGγ accelerates melanoma formation by regulating Wnt/β‐catenin signalling pathway

Abstract

It has been reported that the proteasome activator REGγ is associated with multiple oncogenic pathways in human cancers. However, the role of REGγ in the development of melanoma and the underlying mechanisms remain unclear. In this study, we attempted to investigate the effects of REGγ on human melanoma cell proliferation in vitro and in vivo. We demonstrated that knockdown of REGγ inhibited melanoma cell growth and arrested melanoma cell at G1 phase. Furthermore, depletion of REGγ also inhibited the xenograft growth of human melanoma. Mechanistically, REGγ activates Wnt/β-catenin signal pathway by degrading GSK-3β in melanoma cell lines and mouse models. Transient knockdown of β-catenin effectively blocked cell proliferation in REGγ wild-type melanoma cells. In human melanoma samples, REGγ was overexpressed and positively correlated with β-catenin levels. This study demonstrates that REGγ is a central molecule in the development of melanoma by regulating Wnt/β-catenin pathway. This suggests that targeting REGγ could be an alternative therapeutic approach for melanoma.

Proteasomes and Several Aspects of Their Heterogeneity Relevant to Cancer

“…The elevated expression of 11Sγ has been reported in several different cancers, including melanoma (218), squamous cell carcinoma (213), laryngeal carcinoma (219), lung, colorectal, thyroid, liver (220–222), endometrial (223), pancreatic (216), and breast cancer (224, 225), and is correlated with metastasis and poor prognosis in patients with liver, breast, and pancreatic cancer (216, 225–227). c-Myc is a transcription factor and a proto-oncogene that is overexpressed in many different tumors.…”

“…Another way that 11Sγ can affect c-Myc is through the regulation of β-catenin accumulation, which is an upstream regulator of c-Myc (213). 11Sγ expression is activated through the MAPK/p38/AP-1 signaling pathway and leads to the activation of Wnt/β-catenin signaling through enhanced degradation of GSK-3β, which is a negative regulator of β-catenin (213, 218). Interestingly, mutant but not wild-type p53 facilitated 11Sγ transcription and stimulated breast, colon and endometrial cancer cell proliferation (223, 228).…”

Lycorine inhibits melanoma cell migration and metastasis mainly through reducing intracellular levels of β‐catenin and matrix metallopeptidase 9

“…Accumulated evidence have shown that β‐catenin was deregulated in various carcinomas including colorectal cancer, ovarian cancer, and lung cancer (Krishnamurthy & Kurzrock, ; Nusse & Clevers, ; B. Wang, Tian, Kalland, Ke, & Qu, ). Contradictory functions of β‐catenin have been found in melanoma (Chen et al, ; Chien et al, ; Damsky et al, ; Hseu et al, ; Spranger, Bao, & Gajewski, ; Zheng, Liu & Pan, ). Chien et al () reported that the activation of Wnt/β‐catenin signaling is correlated with the decreased expression of proliferation markers.…”

Comprehensive circRNA expression profile and construction of circRNA‐associated ceRNA network in fur skin

“…The KEGG pathway of different host genes of circRNAs in both embryo 15 days and postnatal 7 days of black fur skin and white fur skin mainly enriched in Jack‐STAT signalling and wnt signalling pathway. Some studies have indicated that the wnt signalling activation addresses the consequences for sensitiveness of melanoma cells . Functional studies are warranted to explore the role of these circRNAs to understand their involvement in relation to their host gene in metabolic pathway.…”