Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-κB Pathway in Melanoma.
Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-κB Pathway in Melanoma.
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DOI：
10.1158/1078-0432.ccr-17-0146
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发表时间：
2017-08-15
期刊：
影响因子：
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通讯作者：
Hoon DSB
中科院分区：
文献类型：
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作者：
Iida Y;Ciechanover A;Marzese DM;Hata K;Bustos M;Ono S;Wang J;Salomon MP;Tran K;Lam S;Hsu S;Nelson N;Kravtsova-Ivantsiv Y;Mills GB;Davies MA;Hoon DSB
NF-κB途径的异常激活可诱导皮肤黑色素瘤更具侵袭性的表型。了解黑色素瘤NF-κB激活的机制可能会为这一途径确定新的靶点。KPC 1是一种E3泛素连接酶，是NF-κB通路的调节因子。本研究的目的是研究调节KPC 1表达的机制及其在黑色素瘤中的临床影响。在临床上充分注释的黑色素瘤组织（组织微阵列; n=137，JWCI组群; n=40）和癌症基因组图谱数据库（TCGA组群，n=370）的大组群中评估KPC 1表达及其表观遗传调控的临床影响。我们利用黑色素瘤细胞系研究了KPC 1和NF-κB之间的功能相互作用，以及KPC 1的表观遗传调控，包括DNA甲基化和microRNA表达。我们证实KPC 1通过将NF-κB1 p105加工成p50，从而调节NF-κ B靶基因表达来抑制黑色素瘤增殖。一致地，与早期阶段（I/II期p=0.013，III期p=0.004）相比，AJCC IV期黑素瘤中KPC 1表达下调，并且低KPC 1表达与IV期黑素瘤中的不良总生存率显著相关（n=137，风险比1.810，p=0.006）。此外，我们的数据显示，miR-155- 5 p的高表达（由其启动子区域的DNA甲基化控制）（TCGA; Pearson's r −0.455，p<0.001）与KPC 1下调显著相关（JWCI; p=0.028，TCGA; p=0.003）。这项研究揭示了与NF-κB通路激活相关的KPC 1的新型表观遗传调控，促进转移性黑色素瘤进展。这些发现表明KPC 1及其表观遗传调控作为治疗诊断靶点的潜在效用。
Abnormal activation of the NF-κB pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-κB activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of NF-κB pathway. The objective of this study was to investigate the mechanisms regulating KPC1 expression and its clinical impact in melanoma. The clinical impact of KPC1 expression and its epigenetic regulation were assessed in large cohorts of clinically well-annotated melanoma tissues (tissue micro-arrays; n=137, JWCI cohort; n=40) and The Cancer Genome Atlas database (TCGA cohort, n=370). Using melanoma cell lines, we investigated the functional interactions between KPC1 and NF-κB, and the epigenetic regulations of KPC1, including DNA methylation and microRNA expression. We verified that KPC1 suppresses melanoma proliferation by processing NF-κB1 p105 into p50, thereby modulating NF-κB-target gene expression. Concordantly, KPC1 expression was down-regulated in AJCC stage IV melanoma compared to early stages (stage I/II p=0.013, stage III p=0.004), and low KPC1 expression was significantly associated with poor overall survival in stage IV melanoma (n=137, Hazard Ratio 1.810, p=0.006). Furthermore, our data showed that high miR-155-5p expression, which is controlled by DNA methylation at its promoter region (TCGA; Pearson’s r −0.455, p<0.001), is significantly associated with KPC1 down-regulation (JWCI; p=0.028, TCGA; p=0.003). This study revealed novel epigenetic regulation of KPC1 associated with NF-κB pathway activation, promoting metastatic melanoma progression. These findings suggest the potential utility of KPC1 and its epigenetic regulation as theranostic targets.