Lysine Demethylase 5A is Required for MYC Driven Transcription in Multiple Myeloma
Lysine Demethylase 5A is Required for MYC Driven Transcription in Multiple Myeloma
复制标题
多发性骨髓瘤中 MYC 驱动的转录需要赖氨酸脱甲基酶 5A
DOI：
10.1158/2643-3230.bcd-20-0108
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发表时间：
2021
影响因子：
11.2
通讯作者：
Durbin A
中科院分区：
文献类型：
--
作者：
Ohguchi H;Park Paul M.C.;wang t;Gryder B E.;Ogiya D;kurata k;zhang x;Li D;pei c;Masuda T;Johansson C;Wimalasena V K;Kim Y;Hino S;Usuki S;Kawano Y;Samur M K;Tai Yu-Tzu;Munshi N C.;Matsuoka M;Ohtsuki S;Nakao M;Minami T;Lauberth S;Khan J;Oppermann U;Durbin A
赖氨酸脱甲基酶5A（KDM 5A）是组蛋白H3赖氨酸4三甲基化（H3 K4 me 3）的负调控因子，H3 K4 me 3是一种与基因转录激活相关的组蛋白标记。我们确定KDM 5A与P-TEFb复合物相互作用，并与MYC合作控制多发性骨髓瘤细胞中的MYC靶向基因。我们开发了一种细胞渗透性和选择性的KDM 5抑制剂JQKD 82，它在体外和体内增加H3 K4 me 3，但矛盾地抑制下游MYC驱动的转录输出。使用基因消融和我们的抑制剂，我们确定KDM 5A通过支持TFIIH（CDK 7）和P-TEFb（CDK 9）介导的RNAPII磷酸化，支持MYC靶基因转录，而不依赖于MYC本身。这些数据确定KDM 5A作为一个独特的脆弱性，在多发性骨髓瘤的功能，通过调节MYC靶基因的转录，并建立JQKD 82作为一种工具化合物，以阻止KDM 5A功能作为一个潜在的治疗策略多发性myeloma. Significance我们描绘的功能KDM 5A激活MYC驱动的转录景观。我们开发了一种细胞可渗透的KDM 5抑制剂，以确定KDM 5A对MYC靶基因表达的激活作用，并在小鼠模型和多发性骨髓瘤患者样本中揭示该化合物的治疗潜力。参见2021年AACR年会的相关视频：https://vimeo.com/554896826
Lysine demethylase 5A (KDM5A) is a negative regulator of histone H3 lysine 4 trimethylation (H3K4me3), a histone mark associated with activate gene transcription. We identify that KDM5A interacts with the P-TEFb complex and cooperates with MYC to control MYC-targeted genes in multiple myeloma cells. We develop a cell-permeable and selective KDM5 inhibitor, JQKD82, that increases H3K4me3 but paradoxically inhibits downstream MYC-driven transcriptional outputin vitroandin vivo. Using genetic ablation together with our inhibitor, we establish that KDM5A supports MYC target gene transcription independent of MYC itself by supporting TFIIH (CDK7)- and P-TEFb (CDK9)–mediated phosphorylation of RNAPII. These data identify KDM5A as a unique vulnerability in multiple myeloma functioning through regulation of MYC target gene transcription and establish JQKD82 as a tool compound to block KDM5A function as a potential therapeutic strategy for multiple myeloma.SignificanceWe delineate the function of KDM5A in activating the MYC-driven transcriptional landscape. We develop a cell-permeable KDM5 inhibitor to define the activating role of KDM5A on MYC target gene expression and implicate the therapeutic potential of this compound in mouse models and multiple myeloma patient samples.See related video from the AACR Annual Meeting 2021:https://vimeo.com/554896826