CDKN2A 双等位基因缺失通过 BRN2 激活引发黑色素瘤侵袭。
Bi-allelic Loss of CDKN2A Initiates Melanoma Invasion via BRN2 Activation.
机构信息
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Dermatology, University of California San Francisco, San Francisco, CA 94115, USA.
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Dermatology, University of California San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California San Francisco, San Francisco, CA 94115, USA.
出版信息
Cancer Cell. 2018 Jul 9;34(1):56-68.e9. doi: 10.1016/j.ccell.2018.05.014.
Loss of the CDKN2A tumor suppressor is associated with melanoma metastasis, but the mechanisms connecting the phenomena are unknown. Using CRISPR-Cas9 to engineer a cellular model of melanoma initiation from primary human melanocytes, we discovered that a lineage-restricted transcription factor, BRN2, is downstream of CDKN2A and directly regulated by E2F1. In a cohort of melanocytic tumors that capture distinct progression stages, we observed that CDKN2A loss coincides with both the onset of invasive behavior and increased BRN2 expression. Loss of the CDKN2A protein product p16 permitted metastatic dissemination of human melanoma lines in mice, a phenotype rescued by inhibition of BRN2. These results demonstrate a mechanism by which CDKN2A suppresses the initiation of melanoma invasion through inhibition of BRN2.
抑癌基因 CDKN2A 的缺失与黑色素瘤转移有关，但这两种现象之间的关联机制尚不清楚。我们利用 CRISPR-Cas9 技术构建了一个源自原代人黑素细胞的黑色素瘤起始的细胞模型，发现一个谱系限制性转录因子 BRN2 是 CDKN2A 的下游靶点，并且直接受 E2F1 的调控。在一组捕获不同进展阶段的黑素瘤肿瘤中，我们观察到 CDKN2A 的缺失与侵袭行为的开始以及 BRN2 表达的增加同时发生。CDKN2A 蛋白产物 p16 的缺失使人类黑色素瘤细胞系在小鼠中发生转移播散，而 BRN2 的抑制作用则挽救了这一表型。这些结果表明，CDKN2A 通过抑制 BRN2 来抑制黑色素瘤侵袭的起始。
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