ATRA-induced NEAT1 upregulation promotes autophagy during APL cell granulocytic differentiation

Doudou Tang; Huihui Wang; Yafeng Jiang; Mingjie Chen; Guangsen Zhang; Shangjie Wu; Yewei Wang

doi:10.1371/journal.pone.0316109

ATRA-induced NEAT1 upregulation promotes autophagy during APL cell granulocytic differentiation

PLoS One. 2024 Dec 23;19(12):e0316109. doi: 10.1371/journal.pone.0316109. eCollection 2024.

Authors

Doudou Tang^{1

2}, Huihui Wang^{3

4}, Yafeng Jiang³, Mingjie Chen⁵, Guangsen Zhang^{3

4}, Shangjie Wu^{1

2}, Yewei Wang^{3

4}

Affiliations

¹ Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
² Hunan Centre for Evidence-based Medicine, Central South University, Changsha, Hunan, China.
³ Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁴ Institute of Molecular Hematology, Central South University, Changsha, Hunan, China.
⁵ Shanghai NewCore Biotechnology Co., Ltd., Minhang District, Shanghai, China.

Abstract

Aims: Acute promyelocytic leukemia (APL) progresses quickly and often leads to early hemorrhagic death. Treatment with all-trans retinoic acid (ATRA) promotes differentiation of APL cells and clinical remission, making APL a potentially curable malignancy. Understanding how ATRA works may lead to new treatments for other types of leukemia. Long non-coding RNA NEAT1 has been implicated in the differentiation of APL cells. This study aims to elucidate the specific role of NEAT1 in the granulocytic differentiation of APL.

Methods: The influence of NEAT1 on autophagy and PML/RARα degradation was assessed using western blot assays. The impact of NEAT1 on the expression of autophagy-related genes was evaluated through quantitative real-time RT-PCR. Mechanistic insights into the role of NEAT1 in modulating autophagy were supported by RNA immunoprecipitation and RNA pulldown assays.

Key findings: Knockdown of NEAT1 suppressed autophagy and attenuated ATRA-induced PML/RARα degradation and granulocytic differentiation of APL cells. Subsequent screening of autophagy-related genes demonstrated that silencing NEAT1 impaired the ATRA-induced upregulation of ATG10 and ATG12. Mechanistic investigations revealed that the RNA-binding protein TAF15 interacted with NEAT1, synergistically stabilizing the mRNA of ATG10 and ATG12. Furthermore, knockdown of NEAT1 impaired the interactions between TAF15 and the mRNAs of ATG10 and ATG12, thereby compromising their mRNA stability.

Significance: Our study elucidates the critical role of NEAT1-mediated autophagy in the differentiation of APL cells and delineates the molecular mechanism by which upregulation of NEAT1 enhances autophagy. Specifically, NEAT1 binds to the RNA-binding protein TAF15, which in turn stabilizes the mRNA of both ATG10 and ATG12.

Copyright: © 2024 Tang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

MeSH terms

Autophagy* / drug effects
Cell Differentiation* / drug effects
Cell Line, Tumor
Granulocytes / drug effects
Granulocytes / metabolism
Humans
Leukemia, Promyelocytic, Acute* / genetics
Leukemia, Promyelocytic, Acute* / metabolism
Leukemia, Promyelocytic, Acute* / pathology
Oncogene Proteins, Fusion / genetics
Oncogene Proteins, Fusion / metabolism
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
Tretinoin* / pharmacology
Up-Regulation* / drug effects

Substances

RNA, Long Noncoding
Tretinoin
NEAT1 long non-coding RNA, human
Oncogene Proteins, Fusion
promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein

Grants and funding

This work was supported by fundings from the Natural Science Foundation of Hunan Province (2022JJ30850 awarded to Y.W.; 2023JJ40850 awarded to D.T.) and Foundation of Health Commission of Hunan Province (D202303047052 awarded to D.T.; W20243031 awarded to Y.W.). The funders had no role in the study design, data collection, data analysis, the decision to publish, or the preparation of the manuscript. There was no additional external funding received for this study.