A20 promotes melanoma progression via the activation of Akt pathway

Abstract

Melanoma is the most life-threatening skin cancer with increasing incidence around the world. Although recent advances in targeted therapy and immunotherapy have brought revolutionary progress of the treatment outcome, the survival of patients with advanced melanoma remains unoptimistic, and metastatic melanoma is still an incurable disease. Therefore, to further understand the mechanism underlying melanoma pathogenesis could be helpful for developing novel therapeutic strategy. A20 is a crucial ubiquitin-editing enzyme implicated immunity regulation, inflammatory responses and cancer pathogenesis. Herein, we report that A20 played an oncogenic role in melanoma. We first found that the expression of A20 was significantly up-regulated in melanoma cell lines. Then, we showed that knockdown of A20 suppressed melanoma cell proliferation in vitro and melanoma growth in vivo through the regulation of cell-cycle progression. Moreover, A20 could potentiate the invasive and migratory capacities of melanoma cell in vitro and melanoma metastasis in vivo by promoting epithelial–mesenchymal transition (EMT). Mechanistically, we found that Akt activation mediated the oncogenic effect of A20 on melanoma development, with the involvement of glycolysis. What’s more, the up-regulation of A20 conferred the acquired resistance to Vemurafenib in BRAF-mutant melanoma. Taken together, we demonstrated that up-regulated A20 promoted melanoma progression via the activation of Akt pathway, and that A20 could be exploited as a potential therapeutic target for melanoma treatment.

Histone demethylase KDM5A promotes tumorigenesis of osteosarcoma tumor

“…Cinobufagin inhibited osteosarcoma cell proliferation and tumorigenesis capability via blocking IL6–OPN–STAT3 signaling pathway 29 . Tumor necrosis factor alpha-induced protein 3 (TNFAIP3), also known as A20, was a ubiquitin-editing enzyme that promotes melanoma cell proliferation in vitro and melanoma growth in vivo through the overexpression of cyclin D and phosphor Rb 30 . IL6 also increased the expression of intercellular adhesion molecule-1 (ICAM-1) and promoted migration in human osteosarcoma cells 31 .…”

“…TGF-β/BMP2 signaling pathways also promoted osteosarcoma cell migration and invasion 40 . Moreover, TNFAIP3 could potentiate the invasive and migratory capacities of melanoma cells in vitro and melanoma metastasis in vivo by promoting epithelial–mesenchymal transition (EMT) 30 . IL6 enhanced lung colonization of OS cells by overexpression of ICAM-1 and promoted tumor metastasis 41 .…”

Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response

“…The involvement of diminished DUB activity in these neurodegenerative disorders may be due in part to the importance of ubiquitin signaling in regulating synaptic function ( 36 ). Many of the DUBs known to be involved in cancers are also redox-sensitive, such as USP7, which has been implicated in liver cancer and leukemia, and A20, which is involved in metastatic cancers ( 238 , 239 , 240 , 241 ). Although much remains to be determined as to the specific roles DUBs play in these diseases and the impact of oxidative stress on them, it is undeniable that their malfunction leads to deregulation of critical pathways within neurons, making them important targets for the development of therapeutics to treat these conditions.…”

Redox regulation of DUBs and its therapeutic implications in cancer

“…Apart from their role in neurological disorders, several redox-sensitive DUBs are also involved in cancer. For instance, redox-sensitive DUBs such as USP7 and A20 are associated with the progression of leukemia, liver, and metastatic cancers [ 278 , 279 ]. DUBs also regulate tumor progression by stabilizing potential cancer checkpoints and T-cell functions in cancer immunity.…”