Interaction of the oncoprotein transcription factor MYC with its chromatin cofactor WDR5 is essential for tumor maintenance
Interaction of the oncoprotein transcription factor MYC with its chromatin cofactor WDR5 is essential for tumor maintenance
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DOI：
10.1073/pnas.1910391116
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发表时间：
2019-12-10
影响因子：
11.1
通讯作者：
Tansey, William P.
中科院分区：
文献类型：
--
作者：
Thomas, Lance R.;Adams, Clare M.;Tansey, William P.
癌蛋白转录因子MYC在大多数癌症中过度表达。其致癌活性的关键是MYC调节驱动和维持恶性状态的基因表达模式的能力。MYC也被认为是一个有效的抗癌靶点，但药物抑制MYC的努力失败了。MYC对辅助因子的依赖性为治疗干预创造了机会，但对于任何辅助因子，这都需要对辅助因子如何与MYC相互作用的结构理解，了解其在MYC功能中所起的作用，并证明破坏辅助因子的相互作用将导致现有癌症的消退。其中一个结构信息可用的辅助因子是WDR5，它与MYC相互作用以促进其向染色质募集。为了探索破坏MYC-WDR5相互作用是否可能成为一种可行的抗癌策略，我们开发了一种Burkitt淋巴瘤系统，该系统允许用野生型MYC替换WDR5结合缺陷或所有已知核MYC功能缺陷的突变体。利用该系统，我们发现WDR5将MYC招募到染色质上，以控制与生物量积累相关的基因的表达。我们进一步表明，在现有癌症的背景下，破坏MYC-WDR5相互作用可以促进体内肿瘤的快速和全面消退。这些观察结果将WDR5与MYC的核心致瘤功能联系起来，并确定，如果可以建立治疗窗口，MYC-WDR5抑制剂可以开发为抗癌药物。
The oncoprotein transcription factor MYC is overexpressed in the majority of cancers. Key to its oncogenic activity is the ability of MYC to regulate gene expression patterns that drive and maintain the malignant state. MYC is also considered a validated anticancer target, but efforts to pharmacologically inhibit MYC have failed. The dependence of MYC on cofactors creates opportunities for therapeutic intervention, but for any cofactor this requires structural understanding of how the cofactor interacts with MYC, knowledge of the role it plays in MYC function, and demonstration that disrupting the cofactor interaction will cause existing cancers to regress. One cofactor for which structural information is available is WDR5, which interacts with MYC to facilitate its recruitment to chromatin. To explore whether disruption of the MYC-WDR5 interaction could potentially become a viable anticancer strategy, we developed a Burkitt's lymphoma system that allows replacement of wild-type MYC for mutants that are defective for WDR5 binding or all known nuclear MYC functions. Using this system, we show that WDR5 recruits MYC to chromatin to control the expression of genes linked to biomass accumulation. We further show that disrupting the MYC-WDR5 interaction within the context of an existing cancer promotes rapid and comprehensive tumor regression in vivo. These observations connect WDR5 to a core tumorigenic function of MYC and establish that, if a therapeutic window can be established, MYC-WDR5 inhibitors could be developed as anticancer agents.