UBE2N Promotes Melanoma Growth via MEK/FRA1/SOX10 Signaling.
UBE2N Promotes Melanoma Growth via MEK/FRA1/SOX10 Signaling.
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DOI：
10.1158/0008-5472.can-18-1040
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发表时间：
2018-11-15
期刊：
影响因子：
11.2
通讯作者：
Zhang JY
中科院分区：
文献类型：
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作者：
Dikshit A;Jin YJ;Degan S;Hwang J;Foster MW;Li CY;Zhang JY
UBE 2N是一种与多种免疫疾病和癌症相关的K63特异性泛素缀合酶。在这里，我们证明了UBE 2N及其伙伴UBE 2 V1和UBE 2 V2在恶性黑色素瘤中高度表达。UBE 2N及其伴侣的沉默显著降低了黑色素瘤细胞增殖和皮下肿瘤生长。这伴随着E-钙粘蛋白，p16和MC 1 R的表达增加和黑色素瘤恶性肿瘤标志物，包括SOX 10，巢蛋白和ABCB 5的表达减少。基于质谱的磷酸化蛋白质组学分析显示，UBE 2N的丢失导致信号转导格局的明显改变：MEK/ERK信号转导受损，FRA 1和SOX 10基因调控因子下调，p53和p16肿瘤抑制因子上调。与抑制UBE 2N和MEK类似，沉默FRA 1降低了SOX 10表达和细胞增殖。相反，外源性表达的活性FRA 1增加pMEK和SOX 10的表达，并恢复锚定非依赖性细胞生长的细胞与UBE 2N损失。全身递送NSC 697923（一种UBE 2N的小分子抑制剂）显著降低黑素瘤异种移植物生长。这些数据表明，UBE 2N是一种新的调节MEK/FRA 1/SOX 10信号级联，是不可缺少的恶性黑色素瘤的生长。我们的研究结果为靶向UBE 2N作为黑色素瘤的潜在治疗策略奠定了基础。
UBE2N is a K63-specific ubiquitin conjugase linked to various immune disorders and cancer. Here we demonstrate that UBE2N and its partners UBE2V1 and UBE2V2 are highly expressed in malignant melanoma. Silencing of UBE2N and its partners significantly decreased melanoma cell proliferation and subcutaneous tumor growth. This was accompanied by increased expression of E-cadherin, p16, and MC1R and decreased expression of melanoma malignancy markers including SOX10, Nestin, and ABCB5. Mass spectrometry-based phosphoproteomic analysis revealed that UBE2N loss resulted in distinct alterations to the signaling landscape: MEK/ERK signaling was impaired, FRA1 and SOX10 gene regulators were downregulated, and p53 and p16 tumor suppressors were upregulated. Similar to inhibition of UBE2N and MEK, silencing FRA1 decreased SOX10 expression and cell proliferation. Conversely, exogenous expression of active FRA1 increased pMEK and SOX10 expression and restored anchorage-independent cell growth of cells with UBE2N loss. Systemic delivery of NSC697923, a small molecule inhibitor of UBE2N, significantly decreased melanoma xenograft growth. These data indicate that UBE2N is a novel regulator of the MEK/FRA1/SOX10 signaling cascade and is indispensable for malignant melanoma growth. Our findings establish the basis for targeting UBE2N as a potential treatment strategy for melanoma.
影响因子：
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作者：
Brun J;Chiu R;Lockhart K;Xiao W;Wouters BG;Gray DA
通讯作者：
Gray DA