PHF6 functions as a tumor suppressor by recruiting methyltransferase SUV39H1 to nucleolar region and offers a novel therapeutic target for PHF6-muntant leukemia.
PHF6 functions as a tumor suppressor by recruiting methyltransferase SUV39H1 to nucleolar region and offers a novel therapeutic target for PHF6-muntant leukemia.
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DOI：
10.1016/j.apsb.2021.10.025
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发表时间：
2022-04
影响因子：
14.5
通讯作者：
Chen, Hongbo
中科院分区：
文献类型：
--
作者：
Tsai, Hsiang-i;Wu, Yanping;Huang, Rui;Su, Dandan;Wu, Yingyi;Liu, Xiaoyan;Wang, Linglu;Xu, Zhanxue;Pang, Yuxin;Sun, Chong;He, Chao;Shu, Fan;Zhu, Haitao;Wang, Dongqing;Cheng, Fang;Huang, Laiqiang;Chen, Hongbo
植物同源结构域样指蛋白6（PHF 6）基因突变与急性髓细胞白血病（AML）和T细胞急性淋巴细胞白血病（T-ALL）密切相关。在这项研究中，我们证明了PHF 6可以结合到核仁染色质上的H3 K9 me 3和H3 K27 me 1，并将组蛋白甲基转移酶SUV 39 H1募集到rDNA位点。PHF 6的缺失导致SUV 39 H1向rDNA基因位点的募集减少，从而导致H3 K9 me 3水平降低和rDNA转录促进。无论是SUV 39 H1或PHF 6的敲低显着减弱的影响，增加H3 K9 me 3和抑制转录诱导的其他相互作用的伴侣过表达的rDNA，从而建立一个相互依赖的关系PHF 6和SUV 39 H1在其控制的rRNA转录。PHF 6临床突变体显著损害了将SUV 39 H1结合和募集到rDNA位点的能力，导致rDNA转录活性增加、体外白血病细胞增殖和体内小鼠异种移植物生长。重要的是，在具有突变形式的PHF 6的临床AML患者中观察到前rRNA水平显著升高。特异性rDNA转录抑制剂CX 5461显著降低了PHF 6缺陷的U937 AML细胞对阿糖胞苷（最常用于治疗AML的药物）的耐药性。总的来说，我们揭示了一种新的分子机制，PHF 6招募甲基转移酶SUV 39 H1在白血病的核仁区，并提供了一个潜在的治疗靶点PHF 6突变型白血病。野生型PHF 6被识别为H3 K9 me 3和H3 K27 me 1，它招募SUV 39 H1催化H3 K9和H3 K27的甲基化以抑制rDNA的转录。当PHF 6突变时，SUV 39 H1不能被募集用于rDNA甲基化，导致不受控制的rDNA转录。
Mutations in the plant homeodomain-like finger protein 6 (PHF6) gene are strongly associated with acute myeloid (AML) and T-cell acute lymphoblastic leukemia (T-ALL). In this study, we demonstrated that PHF6 can bind to H3K9me3 and H3K27me1 on the nucleolar chromatin and recruit histone methyltransferase SUV39H1 to the rDNA locus. The deletion of PHF6 caused a decrease in the recruitment of SUV39H1 to rDNA gene loci, resulting in a reduction in the level of H3K9me3 and the promotion of rDNA transcription. The knockdown of either SUV39H1 or PHF6 significantly attenuated the effects of increase in H3K9me3 and suppressed the transcription of rDNA induced by the overexpression of the other interacting partner, thereby establishing an interdependent relationship between PHF6 and SUV39H1 in their control of rRNA transcription. The PHF6 clinical mutants significantly impaired the ability to bind and recruit SUV39H1 to the rDNA loci, resulting in an increase in rDNA transcription activity, the proliferation of in vitro leukemia cells, and the growth of in vivo mouse xenografts. Importantly, significantly elevated levels of pre-rRNA were observed in clinical AML patients who possessed a mutated version of PHF6. The specific rDNA transcription inhibitor CX5461 significantly reduced the resistance of U937 AML cells deficient in PHF6 to cytarabine, the drug that is most commonly used to treat AML. Collectively, we revealed a novel molecular mechanism by which PHF6 recruits methyltransferase SUV39H1 to the nucleolar region in leukemia and provided a potential therapeutic target for PHF6-mutant leukemia. Wild-type PHF6 is recognized as H3K9me3 and H3K27me1, and it recruits SUV39H1 to catalyze the methylation of H3K9 and H3K27 to inhibit the transcription of rDNA. When PHF6 is mutated, SUV39H1 cannot be recruited for rDNA methylation, resulting in uncontrolled rDNA transcription.
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影响因子：
3.5
作者：
Todd MA;Ivanochko D;Picketts DJ
通讯作者：
Picketts DJ
影响因子：
3.2
作者：
Chao, Mwe Mwe;Todd, Matthew A.;Kontny, Udo;Neas, Katherine;Sullivan, Michael J.;Hunter, Alasdair G.;Picketts, David J.;Kratz, Christian P.
通讯作者：
Kratz, Christian P.
影响因子：
16.8
作者：
Musselman, Catherine A.;Lalonde, Marie-Eve;Cote, Jacques;Kutateladze, Tatiana G.
通讯作者：
Kutateladze, Tatiana G.
影响因子：
3.3
作者：
Forestan C;Farinati S;Rouster J;Lassagne H;Lauria M;Dal Ferro N;Varotto S
通讯作者：
Varotto S
影响因子：
4.4
作者：
Todd, Matthew A. M.;Picketts, David J.
通讯作者：
Picketts, David J.