Department of Pathology, Lhasa People's Hospital, Tibet Autonomous Region, Lhasa, 850000, PR China.
Department of General Surgery, Hunan Province Brain Hospital, Changsha, 410007, PR China.
Exp Cell Res. 2021 May 1;402(1):112506. doi: 10.1016/j.yexcr.2021.112506. Epub 2021 Jan 29.
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.
越来越多的证据表明，KLF5 在人类癌症中的表达异常，但其在黑色素瘤中的作用尚未确定。本研究旨在探讨 KLF5 在黑色素瘤增殖和转移中的作用。通过生物信息学分析检测黑色素瘤中的 WWP1、BAP1 和 KLF5 的表达，然后在黑色素瘤患者和癌细胞的临床组织中进行表达测定。用表达 KLF5 或 BAP1 的慢病毒感染癌细胞，检测 PI3K、AKT 和 mTOR 的表达，并观察自噬。当测量肿瘤生长并检测自噬相关蛋白时，将处理过的细胞注射到小鼠中。将表达 WWP1 和 Ub-K48 的质粒共转染到处理过的黑色素瘤细胞中，然后进行免疫沉淀测定以确定 KLF5、WWP1 和 BAP1 之间的相互作用。WWP1 在黑色素瘤细胞和组织中表达水平较低，而 KLF5 表达水平较高，与不良预后呈正相关。KLF5 促进黑色素瘤细胞恶性表型，并抑制自噬。有趣的是，KLF5 有助于激活 PI3K-AKT-mTOR 信号通路，从而抑制黑色素瘤细胞中的自噬。WWP1 介导 KLF5 的 K48 连接泛素化，促进其降解，BAP1 拮抗这种修饰并稳定 KLF5 蛋白表达。此外，BAP1 促进体内黑色素瘤的 KLF5 介导生长。总之，BAP1 拮抗 WWP1 介导的 KLF5 泛素化，抑制自噬并促进黑色素瘤的发展。
