Usp9x regulates Ets-1 ubiquitination and stability to control NRAS expression and tumorigenicity in melanoma.
Usp9x regulates Ets-1 ubiquitination and stability to control NRAS expression and tumorigenicity in melanoma.
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DOI：
10.1038/ncomms14449
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发表时间：
2017-02-15
影响因子：
16.6
通讯作者：
Donato NJ
中科院分区：
文献类型：
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作者：
Potu H;Peterson LF;Kandarpa M;Pal A;Sun H;Durham A;Harms PW;Hollenhorst PC;Eskiocak U;Talpaz M;Donato NJ
ETS转录因子在癌症中通常通过染色体易位、过度表达或翻译后修饰而失调，以诱导致瘤性所必需的基因表达程序。有针对性地破坏这些蛋白质可能具有治疗作用。在此，我们报告 Ets-1 破坏受到去泛素化酶 Usp9x 的调节，并对转移性黑色素瘤的致瘤程序产生重大影响。 Ets-1 去泛素化可阻止其蛋白酶体破坏并增强致瘤性，这可以通过 Usp9x 敲低或抑制来逆转。 Usp9x 和 Ets-1 水平在黑色素瘤中同时升高，与正常皮肤或良性皮肤病变相比，在转移性肿瘤中检测到的水平最高。值得注意的是，Ets-1 是由 BRAF 或 MEK 激酶抑制诱导的，导致 NRAS 表达增加，这可以通过 Usp9x 失活以及 Usp9x 和 MEK 抑制剂的治疗组合完全抑制黑色素瘤生长来阻断。因此，Usp9x 调节 Ets-1/NRAS 调节网络，并可能具有生物学和治疗意义。 Usp9x 是一种去泛素化酶，在黑色素瘤中表达发生改变；然而，其在这方面的功能贡献尚不清楚。作者在此表明，Usp9x 调节转录因子 Ets-1 的稳定性，进而通过增加 NRAS 的表达来影响转移性黑色素瘤。
ETS transcription factors are commonly deregulated in cancer by chromosomal translocation, overexpression or post-translational modification to induce gene expression programs essential in tumorigenicity. Targeted destruction of these proteins may have therapeutic impact. Here we report that Ets-1 destruction is regulated by the deubiquitinating enzyme, Usp9x, and has major impact on the tumorigenic program of metastatic melanoma. Ets-1 deubiquitination blocks its proteasomal destruction and enhances tumorigenicity, which could be reversed by Usp9x knockdown or inhibition. Usp9x and Ets-1 levels are coincidently elevated in melanoma with highest levels detected in metastatic tumours versus normal skin or benign skin lesions. Notably, Ets-1 is induced by BRAF or MEK kinase inhibition, resulting in increased NRAS expression, which could be blocked by inactivation of Usp9x and therapeutic combination of Usp9x and MEK inhibitor fully suppressed melanoma growth. Thus, Usp9x modulates the Ets-1/NRAS regulatory network and may have biologic and therapeutic implications. Usp9x is a deubiquitinating enzyme with altered expression in melanoma; however its functional contribution in this context is not clear. Here the authors show that Usp9x regulates the stability of the transcription factor Ets-1 that in turn impacts metastatic melanoma through increased expression of NRAS.