ZBTB7A Suppresses Melanoma Metastasis by Transcriptionally Repressing MCAM.
ZBTB7A Suppresses Melanoma Metastasis by Transcriptionally Repressing MCAM.
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DOI：
10.1158/1541-7786.mcr-15-0169
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发表时间：
2015-08
期刊：
影响因子：
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通讯作者：
Yuan ZM
中科院分区：
文献类型：
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作者：
Liu XS;Genet MD;Haines JE;Mehanna EK;Wu S;Chen HI;Chen Y;Qureshi AA;Han J;Chen X;Fisher DE;Pandolfi PP;Yuan ZM
黑色素瘤的过度转移倾向使其成为最致命的皮肤癌形式，但转移的潜在机制仍然难以捉摸。在这里，癌症基因组数据集的挖掘发现了染色体19p13.3的频繁丢失和转移性黑色素瘤中锌指转录因子ZBTB7A的相关下调。ZBTB7A调节基因的功能评估鉴定了MCAM，其编码黑色素瘤转移的关键粘附蛋白。使用整合的方法，它表明，ZBTB7A直接结合到启动子和转录抑制MCAM的表达，建立ZBTB7A作为一个真正的MCAM的转录抑制因子。一致地，ZBTB7A的下调导致MCAM的显著上调和增强的黑素瘤细胞侵袭和转移。ZBTB7A和MCAM表达与黑色素瘤转移的负相关性用来自人黑色素瘤标本分析的数据进一步验证。这些结果共同揭示了ZBTB7A在黑色素瘤转移的负调控中的先前未被认识的作用，并具有重要的临床意义。
The excessive metastatic propensity of melanoma makes it the most deadly form of skin cancer, yet the underlying mechanism of metastasis remains elusive. Here, mining of cancer genome datasets discovered a frequent loss of chromosome 19p13.3 and associated down-regulation of the zinc finger transcription factor ZBTB7A in metastatic melanoma. Functional assessment of ZBTB7A-regulated genes identified MCAM, which encodes an adhesion protein key to melanoma metastasis. Using an integrated approach, it is demonstrated that ZBTB7A directly binds to the promoter and transcriptionally represses the expression of MCAM, establishing ZBTB7A as a bona fide transcriptional repressor of MCAM. Consistently, down-regulation of ZBTB7A results in marked upregulation of MCAM and enhanced melanoma cell invasion and metastasis. An inverse correlation of ZBTB7A and MCAM expression in association with melanoma metastasis is further validated with data from analysis of human melanoma specimens. Together these results uncover a previously unrecognized role of ZBTB7A in negative regulation of melanoma metastasis and have important clinical implications.