2. Academic Validation
  3. Deubiquitinase USP9X stabilizes RNA m6A demethylase ALKBH5 and promotes acute myeloid leukemia cell survival

Deubiquitinase USP9X stabilizes RNA m6A demethylase ALKBH5 and promotes acute myeloid leukemia cell survival

  • J Biol Chem. 2023 Jul 14;105055. doi: 10.1016/j.jbc.2023.105055.
Peipei Wang 1,  Jing Wang 2,  Shuxin Yao 1,  Manman Cui 1,  Ying Cheng 1,  Weidong Liu 2,  Zhuying Gao 1,  Jin Hu 1,  Jinfang Zhang 3,  Haojian Zhang 4
Affiliations

Affiliations

  • 1 The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education，School & Hospital of Stomatology, Medical Research Institute, Wuhan University, Wuhan, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.
  • 2 The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education，School & Hospital of Stomatology, Medical Research Institute, Wuhan University, Wuhan, China.
  • 3 Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.
  • 4 The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education，School & Hospital of Stomatology, Medical Research Institute, Wuhan University, Wuhan, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. Electronic address: haojian_zhang@whu.edu.cn.
PMID: 37454738 DOI: 10.1016/j.jbc.2023.105055
Abstract

Post-translational modifications including protein ubiquitination regulate a plethora of cellular processes in distinct manners. RNA m6A is the most abundant post-transcriptional modification on mammalian mRNAs, and plays important roles in various physiological and pathological conditions including hematologic malignancies. We previously determined that the RNA m6A eraser ALKBH5 is necessary for the maintenance of acute myeloid leukemia (AML) stem cell function, but the post-translational modifications involved in ALKBH5 regulation remain elusive. Here, we show that Deubiquitinase USP9X stabilizes ALKBH5 and promotes AML cell survival. Through the use of mass spectrometry as an unbiased approach, we identify USP9X and confirm that it directly binds to ALKBH5. USP9X stabilizes ALKBH5 by removing the K48-linked polyubiquitin chain at K57. Using human myeloid leukemia cells and a murine AML model, we find that genetic knockdown or pharmaceutical inhibition of USP9X inhibits leukemia cell proliferation, induces Apoptosis, and delays AML development. Ectopic expression of ALKBH5 partially mediates the function of USP9X in AML. Overall, this study uncovers Deubiquitinase USP9X as a key for stabilizing ALKBH5 expression, and reveals the important role of USP9X in AML, which provides a promising therapeutic strategy for AML treatment in the clinic.

Keywords

ALKBH5; Acute myeloid leukemia; Deubiquitination; RNA m(6)A; USP9X.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z