PHF6 functions as a tumor suppressor by recruiting methyltransferase SUV39H1 to nucleolar region and offers a novel therapeutic target for PHF6-muntant leukemia.

Autor:	Tsai HI; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China.; Department of Medical Imaging, the Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China., Wu Y; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China., Huang R; Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China., Su D; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China., Wu Y; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China., Liu X; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China., Wang L; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China., Xu Z; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China., Pang Y; School of Traditional Medicine Materials Resource, Guangdong Pharmaceutical University, Yunfu 527322, China., Sun C; Immune Regulation in Cancer, German Cancer Research Center, Heidelberg 69120, Germany., He C; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China., Shu F; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China., Zhu H; Department of Medical Imaging, the Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China., Wang D; Department of Medical Imaging, the Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China., Cheng F; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China., Huang L; The Shenzhen Key Lab of Gene and Antibody Therapy, Center for Biotechnology & Biomedicine, Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China., Chen H; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China.
Jazyk:	angličtina
Zdroj:	Acta pharmaceutica Sinica. B [Acta Pharm Sin B] 2022 Apr; Vol. 12 (4), pp. 1913-1927. Date of Electronic Publication: 2021 Oct 30.
DOI:	10.1016/j.apsb.2021.10.025
Abstrakt:	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. (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)
Databáze:	MEDLINE
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