BAP1 antagonizes WWP1-mediated transcription factor KLF5 ubiquitination and inhibits autophagy to promote melanoma progression.

Accumulating evidence revealed the abnormal expression of KLF5 in human cancers while its role in melanoma remains uncharacterized. This study aimed to explore the role of KLF5 in the proliferation and metastasis of melanoma. Bioinformatics analysis was performed to detect WWP1, BAP1 and KLF5 expression in melanoma, followed by expression determination on clinical tissues from melanoma patients and cancer cells. The cancer cells were infected with lentivirus expressing KLF5 or BAP1 while PI3K, AKT and mTOR expression was detected and autophagy was observed. Treated cells were injected to mice when tumor growth was measured and autophagy-related protein was detected. Plasmids expressing WWP1 and Ub-K48 were co-transfected into treated melanoma cells while immunoprecipitation assay was performed to determine the interaction among KLF5, WWP1, and BAP1. WWP1 was poorly expressed in melanoma cells and tissues whereas KLF5 was highly expressed and was positively correlated to poor prognosis. KLF5 promoted melanoma cell malignant phenotypes as well as inhibited autophagy. Interestingly, KLF5 contributed to activation of PI3K-AKT-mTOR signaling pathway, thereby inhibiting autophagy in melanoma cells. WWP1 mediated K48-linked ubiquitination of KLF5 to promote its degradation, and BAP1 antagonized this modification and stabilized KLF5 protein expression. Besides, BAP1 promoted KLF5-mediated growth of melanoma in vivo. Taken altogether, BAP1 antagonized WWP1-mediated ubiquitination of KLF5 to inhibit autophagy and promote melanoma development.

Jia X ，Chen H ，Ren Y ，Dejizhuoga ，Gesangyuzhen ，Gao N ，Feng H ，Huang W ，Liao Y ，Yu H ... -  《-》

TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes breast cell proliferation and tumorigenesis.

Zhao D ，Zhi X ，Zhou Z ，Chen C ... -  《-》

BAP1 promotes breast cancer cell proliferation and metastasis by deubiquitinating KLF5.

Qin J ，Zhou Z ，Chen W ，Wang C ，Zhang H ，Ge G ，Shao M ，You D ，Fan Z ，Xia H ，Liu R ，Chen C ... -  《Nature Communications》

Human Kruppel-like factor 5 is a target of the E3 ubiquitin ligase WWP1 for proteolysis in epithelial cells.

Chen C ，Sun X ，Guo P ，Dong XY ，Sethi P ，Cheng X ，Zhou J ，Ling J ，Simons JW ，Lingrel JB ，Dong JT ... -  《JOURNAL OF BIOLOGICAL CHEMISTRY》

BAP1 promotes viability and migration of ECA109 cells through KLF5/CyclinD1/FGF-BP1.

More than 40 000 patients worldwide die from esophageal cancer annually. The 5-year survival rate of patients is only ~ 15-20%, and thus, there is an ongoing need to improve diagnosis and treatment of esophageal cancer. Breast cancer type 1 susceptibility protein (BRCA1)-associated protein (BAP1) is a marker of poor prognosis in several cancers, including uveal melanoma, renal cell carcinoma, cholangiocarcinoma, non-small cell lung cancer, and colorectal cancer. BAP1 mutations are early and rare events in esophageal carcinoma, but the involvement of BAP1 in progression of esophageal carcinoma is unclear. Here, we report that cell proliferation and migration were significantly enhanced in esophageal carcinoma ECA109 cells overexpressing BAP1, while they were diminished upon BAP1 knockdown. In addition, the expression of Krüppel-like factor 5 (KLF5), CyclinD1, and FGF-BP1 was increased by BAP1 overexpression and decreased by BAP1 knockdown. Our data suggest that BAP1 promotes cell proliferation and migration, and enhances the expression of KLF5 and its downstream genes, including CyclinD1 and FGF-BP1, in the esophageal carcinoma cell line ECA109.

Wang F ，Luo M ，Qu H ，Cheng Y ... -  《FEBS Open Bio》