Kuphal Silke, Schneider Nadja, Massoumi Ramin, Hellerbrand Claus, Bosserhoff Anja Katrin
Emil-Fischer-Center, Institute of Biochemistry, Friedrich Alexander University Erlangen-Nuremberg, D-91054 Erlangen, Germany.
Department of Laboratory Medicine, Translational Cancer Research, Lund University, SE-221 00 Lund, Sweden.
Oncol Lett. 2017 Dec;14(6):7262-7268. doi: 10.3892/ol.2017.7120. Epub 2017 Oct 3.
CYLD lysine 63 deubiquitinase (CYLD) was originally identified as a tumor suppressor that is mutated in familial cylindromatosis. Unlike in cylindromatosis, downregulation of the deubiquitinase CYLD in melanoma, a highly aggressive tumor, is not caused by mutations in the gene, but rather by a constitutive and high expression of the snail family transcriptional repressor 1 (SNAIL1). A reduced CYLD level leads to B-cell lymphoma-3/p50/p52-dependent nuclear factor-κB activation, which in turn triggers the expression of genes such as cyclin D1 and N-cadherin. Elevated levels of cyclin D1 and N-cadherin promote melanoma proliferation and invasion. By analyzing the regulation of CYLD expression in melanocytes, the present study identified a signaling pathway that is regulated in response to ultraviolet B (UVB) radiation in melanocytes. UVB light leads to an extracellular signal-regulated kinase-mediated induction of SNAIL1 and subsequent downregulation of expression in normal human epithelial melanocytes. The UVB-mediated suppression of CYLD in melanocytes may have a key role in the reaction to UV stimuli, and may also potentially be involved in the early malignant transformation processes.
CYLD赖氨酸63去泛素化酶（CYLD）最初被鉴定为一种在家族性圆柱瘤中发生突变的肿瘤抑制因子。与圆柱瘤不同，在黑色素瘤（一种侵袭性很强的肿瘤）中，去泛素化酶CYLD的下调并非由该基因的突变引起，而是由蜗牛家族转录抑制因子1（SNAIL1）的组成性高表达所致。CYLD水平降低会导致B细胞淋巴瘤-3/p50/p52依赖性核因子κB激活，进而触发细胞周期蛋白D1和N-钙黏蛋白等基因的表达。细胞周期蛋白D1和N-钙黏蛋白水平升高会促进黑色素瘤的增殖和侵袭。通过分析黑色素细胞中CYLD表达的调控，本研究确定了一条在黑色素细胞中响应紫外线B（UVB）辐射而受到调控的信号通路。UVB光会导致细胞外信号调节激酶介导的SNAIL1诱导以及正常人上皮黑色素细胞中CYLD表达的随后下调。UVB介导的黑色素细胞中CYLD的抑制可能在对UV刺激的反应中起关键作用，并且也可能潜在地参与早期恶性转化过程。
