Hypoxia-induced HIF1α targets in melanocytes reveal a molecular profile associated with poor melanoma prognosis.
Hypoxia-induced HIF1α targets in melanocytes reveal a molecular profile associated with poor melanoma prognosis.
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DOI：
10.1111/pcmr.12579
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发表时间：
2017-05
影响因子：
4.3
通讯作者：
Pavan WJ
中科院分区：
文献类型：
--
作者：
Loftus SK;Baxter LL;Cronin JC;Fufa TD;NISC Comparative Sequencing Program;Pavan WJ
低氧和HIF 1 α信号传导指导组织特异性基因应答，调节肿瘤进展、侵袭和转移。通过整合HIF 1 α敲低和缺氧诱导的基因表达变化，本研究鉴定了黑素细胞特异性的HIF 1 α依赖性/缺氧响应性基因表达特征。将这些基因表达变化与HIF 1 α ChIP-Seq分析整合，在黑素细胞中鉴定出81个HIF 1 α直接靶基因。通过逻辑回归（P值=0.0013）和ROC曲线分析（AUC= 0.826，P值<0.0001），10个HIF 1 α直接靶点- GAPDH、PKM、PPAT、DARS、DTWD 1、SEH 1 L、ZNF 292、RLF、AGTRAP和GPC 6-的表达水平与黑色素瘤中无病状态（DFS）的时间缩短显著相关。这种HIF 1 α调节的特征定义了缺氧条件下黑素细胞的特异性反应，并证明了HIF 1 α作为侵入性细胞状态守门人在调节细胞代谢、染色质和转录调节、血管形成和侵袭中的作用。
Hypoxia and HIF1α signaling direct tissue-specific gene responses regulating tumor progression, invasion and metastasis. By integrating HIF1α knockdown and hypoxia-induced gene expression changes, this study identifies a melanocyte-specific, HIF1α-dependent/hypoxia-responsive gene expression signature. Integration of these gene expression changes with HIF1α ChIP-Seq analysis identifies 81 HIF1α direct target genes in melanocytes. The expression levels for ten of the HIF1α direct targets – GAPDH, PKM, PPAT, DARS, DTWD1, SEH1L, ZNF292, RLF, AGTRAP, and GPC6 – are significantly correlated with reduced time of Disease Free Status (DFS) in melanoma by logistic regression (P-value =0.0013) and ROC curve analysis (AUC= 0.826, P-value<0.0001). This HIF1α-regulated profile defines a melanocyte-specific response under hypoxia, and demonstrates the role of HIF1α as an invasive cell state gatekeeper in regulating cellular metabolism, chromatin and transcriptional regulation, vascularization and invasion.