HDAC1/3-dependent Moderate Liquid-liquid Phase Separation of YY1 Promotes METTL3 Expression and AML Cell Proliferation

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2022 Nov 24

PMID 36424383

Authors

Meng Li

Mingying Li

Yuan Xia

Guosheng Li

Xiuhua Su

Dongmei Wang

Jingjing Ye

Fei Lu

Tao Sun

Chunyan Ji

Affiliations

Soon will be listed here.

Abstract

Methyltransferase-like protein 3 (METTL3) plays critical roles in acute myeloid leukemia (AML) progression, however, the mechanism of abnormal overexpression of METTL3 in AML remain elusive. In the current study, we uncovered that Yin Yang 1 (YY1) binds to the promoter region of METTL3 as a transcription factor and promotes its expression, which in turn enhances the proliferation of AML cells. Mechanistically, YY1 binds to HDAC1/3 and regulates METTL3 expression in a moderate liquid-liquid phase separation (LLPS) manner. After mutation of the HDAC-binding site of YY1 or HDAC inhibitor (HDACi) treatment, YY1 was separated from HDAC1/3, which resulted in an excessive LLPS state, thereby inhibiting the expression of METTL3 and the proliferation of AML cells. In conclusion, our study clarified the regulatory mechanism of the abnormal expression of METTL3 in AML, revealed the precise "Yin-Yang" regulatory mechanism of YY1 from the perspective of LLPS degree, and provided new ideas for the precise diagnosis and treatment of AML.

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References

Zeng C, Huang W, Li Y, Weng H . Roles of METTL3 in cancer: mechanisms and therapeutic targeting. J Hematol Oncol. 2020; 13(1):117. PMC: 7457244. DOI: 10.1186/s13045-020-00951-w. View

Weill L, Shestakova E, Bonnefoy E . Transcription factor YY1 binds to the murine beta interferon promoter and regulates its transcriptional capacity with a dual activator/repressor role. J Virol. 2003; 77(5):2903-14. PMC: 149748. DOI: 10.1128/jvi.77.5.2903-2914.2003. View

Culp-Hill R, DAlessandro A, Pietras E . Extinguishing the Embers: Targeting AML Metabolism. Trends Mol Med. 2020; 27(4):332-344. PMC: 8005405. DOI: 10.1016/j.molmed.2020.10.001. View

Wang W, Qiao S, Li G, Cheng J, Yang C, Zhong C . A histidine cluster determines YY1-compartmentalized coactivators and chromatin elements in phase-separated enhancer clusters. Nucleic Acids Res. 2022; 50(9):4917-4937. PMC: 9122595. DOI: 10.1093/nar/gkac233. View

Chen M, Wei L, Law C, Tsang F, Shen J, Cheng C . RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2. Hepatology. 2017; 67(6):2254-2270. DOI: 10.1002/hep.29683. View

Thomas M, Seto E . Unlocking the mechanisms of transcription factor YY1: are chromatin modifying enzymes the key?. Gene. 1999; 236(2):197-208. DOI: 10.1016/s0378-1119(99)00261-9. View

Dong X, Xu X, Guan Y . LncRNA LINC00899 promotes progression of acute myeloid leukaemia by modulating miR-744-3p/YY1 signalling. Cell Biochem Funct. 2020; 38(7):955-964. DOI: 10.1002/cbf.3521. View

Han J, Wang J, Yang X, Yu H, Zhou R, Lu H . METTL3 promote tumor proliferation of bladder cancer by accelerating pri-miR221/222 maturation in m6A-dependent manner. Mol Cancer. 2019; 18(1):110. PMC: 6588935. DOI: 10.1186/s12943-019-1036-9. View

Dignon G, Zheng W, Kim Y, Mittal J . Temperature-Controlled Liquid-Liquid Phase Separation of Disordered Proteins. ACS Cent Sci. 2019; 5(5):821-830. PMC: 6535772. DOI: 10.1021/acscentsci.9b00102. View

10.

Verheul T, van Hijfte L, Perenthaler E, Barakat T . The Why of YY1: Mechanisms of Transcriptional Regulation by Yin Yang 1. Front Cell Dev Biol. 2020; 8:592164. PMC: 7554316. DOI: 10.3389/fcell.2020.592164. View

11.

Sarvagalla S, Kolapalli S, Vallabhapurapu S . The Two Sides of YY1 in Cancer: A Friend and a Foe. Front Oncol. 2019; 9:1230. PMC: 6879672. DOI: 10.3389/fonc.2019.01230. View

12.

Gordon S, Akopyan G, Garban H, Bonavida B . Transcription factor YY1: structure, function, and therapeutic implications in cancer biology. Oncogene. 2005; 25(8):1125-42. DOI: 10.1038/sj.onc.1209080. View

13.

Li Z, Cheng J, Song Y, Li H, Zheng J . LncRNA SNHG5 upregulation induced by YY1 contributes to angiogenesis via miR-26b/CTGF/VEGFA axis in acute myelogenous leukemia. Lab Invest. 2020; 101(3):341-352. DOI: 10.1038/s41374-020-00519-9. View

14.

Saito M, Hess D, Eglinger J, Fritsch A, Kreysing M, Weinert B . Acetylation of intrinsically disordered regions regulates phase separation. Nat Chem Biol. 2018; 15(1):51-61. DOI: 10.1038/s41589-018-0180-7. View

15.

Lin Z, Hsu P, Xing X, Fang J, Lu Z, Zou Q . Mettl3-/Mettl14-mediated mRNA N-methyladenosine modulates murine spermatogenesis. Cell Res. 2017; 27(10):1216-1230. PMC: 5630681. DOI: 10.1038/cr.2017.117. View

16.

Sabari B, DallAgnese A, Boija A, Klein I, Coffey E, Shrinivas K . Coactivator condensation at super-enhancers links phase separation and gene control. Science. 2018; 361(6400). PMC: 6092193. DOI: 10.1126/science.aar3958. View

17.

Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millan-Zambrano G, Robson S . Promoter-bound METTL3 maintains myeloid leukaemia by mA-dependent translation control. Nature. 2017; 552(7683):126-131. PMC: 6217924. DOI: 10.1038/nature24678. View

18.

Chen Y, Jacamo R, Konopleva M, Garzon R, Croce C, Andreeff M . CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia. J Clin Invest. 2013; 123(6):2395-407. PMC: 3668829. DOI: 10.1172/JCI66553. View

19.

Dao T, Kolaitis R, Kim H, ODonovan K, Martyniak B, Colicino E . Ubiquitin Modulates Liquid-Liquid Phase Separation of UBQLN2 via Disruption of Multivalent Interactions. Mol Cell. 2018; 69(6):965-978.e6. PMC: 6181577. DOI: 10.1016/j.molcel.2018.02.004. View

20.

Atchison M, Basu A, Zaprazna K, Papasani M . Mechanisms of Yin Yang 1 in oncogenesis: the importance of indirect effects. Crit Rev Oncog. 2012; 16(3-4):143-61. PMC: 3417111. DOI: 10.1615/critrevoncog.v16.i3-4.20. View