Histone Deacetylase HDAC2 Regulates MicroRNA-125a Expression in Neuroblastoma

Overview

Journal Brain Behav

Specialty Psychology

Date 2022 Jan 21

PMID 35060363

Authors

Denghui Liu

Xianglian Tang

Zhao Huang

Jiabing Wen

Yuxiang Zhou

Affiliations

Soon will be listed here.

Abstract

Background: Neuroblastoma (NB) is an infrequent childhood malignancy of the peripheral sympathetic nervous system and is accountable for about 10% of pediatric tumors. microRNA (miR)-125a has been implicated to serve as a tumor suppressor in various cancers. Herein, we set out to ascertain whether miR-125a exerts antitumor effects in NB.

Methods: Downregulated miRNAs were identified by miRNA microarray analysis of NB tissues and paracancerous tissues. The expression of miR-125a in NB tissues and cells was detected by reverse transcription-quantitative (RT-q) PCR, followed by prognostic analysis. Gene Ontology (GO) enrichment analysis was performed on target genes of differentially expressed miRNAs. Cell proliferation, apoptosis, and differentiation were detected by cell counting kit-8 (CCK-8), Hoechst staining, immunofluorescence, and western blot. NB cells were injected into nude mice to detect tumorigenic, apoptotic, and differentiation activities in vivo. Dual-luciferase assay and chromatin immunoprecipitation (ChIP) were carried out to verify the binding relationship between miR-125a and PHOX2B or histone deacetylases 2 (HDAC2), respectively. Finally, rescue experiments were conducted.

Results: miR-125a was downregulated in NB tissues and cells, which was associated with poor prognosis. miR-125a reduced NB cell proliferation and augmented apoptosis and differentiation. NB cells with miR-125a overexpression decreased cell tumorigenesis and increased apoptosis and differentiation in xenograft tumor tissues. miR-125a targeted PHOX2B, which was highly expressed in NB tissues and cells. HDAC2, highly expressed in NB tissues and cells, repressed miR-125a transcription through histone deacetylation. Overexpression of HDAC2 or PHOX2B rescued the effects of miR-125a on NB cell proliferation, apoptosis, and differentiation.

Conclusion: HDAC2 inhibited miR-125a transcription through deacetylation, and miR-125a suppressed NB development through binding to PHOX2B.

Citing Articles

HDAC2 as a target for developing anti-cancer drugs.

Jo H, Shim K, Kim H, Jung H, Jeoung D Comput Struct Biotechnol J. 2023; 21:2048-2057.

PMID: 36968022 PMC: 10030825. DOI: 10.1016/j.csbj.2023.03.016.

Histone deacetylase HDAC2 regulates microRNA-125a expression in neuroblastoma.

Liu D, Tang X, Huang Z, Wen J, Zhou Y Brain Behav. 2022; 12(2):e2401.

PMID: 35060363 PMC: 8865159. DOI: 10.1002/brb3.2401.

References

Huang W, Tsai Y, Chen S, Kuo C, Kuo Y, Lee K . HDAC2 and HDAC5 Up-Regulations Modulate Survivin and miR-125a-5p Expressions and Promote Hormone Therapy Resistance in Estrogen Receptor Positive Breast Cancer Cells. Front Pharmacol. 2018; 8:902. PMC: 5736991. DOI: 10.3389/fphar.2017.00902. View

Zhang Y, Xue C, Zhu X, Zhu X, Xian H, Huang Z . Suppression of microRNA-125a-5p upregulates the TAZ-EGFR signaling pathway and promotes retinoblastoma proliferation. Cell Signal. 2016; 28(8):850-60. DOI: 10.1016/j.cellsig.2016.04.002. View

Zammit V, Baron B, Ayers D . MiRNA Influences in Neuroblast Modulation: An Introspective Analysis. Genes (Basel). 2018; 9(1). PMC: 5793179. DOI: 10.3390/genes9010026. View

Witt O, Deubzer H, Milde T, Oehme I . HDAC family: What are the cancer relevant targets?. Cancer Lett. 2008; 277(1):8-21. DOI: 10.1016/j.canlet.2008.08.016. View

Zhao G, Wang G, Bai H, Li T, Gong F, Yang H . Targeted inhibition of HDAC8 increases the doxorubicin sensitivity of neuroblastoma cells via up regulation of miR-137. Eur J Pharmacol. 2017; 802:20-26. DOI: 10.1016/j.ejphar.2017.02.035. View

Thwin K, Ishida T, Uemura S, Yamamoto N, Lin K, Tamura A . Level of Seven Neuroblastoma-Associated mRNAs Detected by Droplet Digital PCR Is Associated with Tumor Relapse/Regrowth of High-Risk Neuroblastoma Patients. J Mol Diagn. 2019; 22(2):236-246. DOI: 10.1016/j.jmoldx.2019.10.012. View

Zhou Q, Feng X, Ye F, Lei F, Jia X, Feng D . miR-27a promotion resulting from silencing of HDAC3 facilitates the recovery of spinal cord injury by inhibiting PAK6 expression in rats. Life Sci. 2020; 260:118098. DOI: 10.1016/j.lfs.2020.118098. View

Berlanga P, Canete A, Castel V . Advances in emerging drugs for the treatment of neuroblastoma. Expert Opin Emerg Drugs. 2017; 22(1):63-75. DOI: 10.1080/14728214.2017.1294159. View

Sun C, Zeng X, Guo H, Wang T, Wei L, Zhang Y . MicroRNA-125a-5p modulates radioresistance in LTEP-a2 non-small cell lung cancer cells by targeting SIRT7. Cancer Biomark. 2019; 27(1):39-49. DOI: 10.3233/CBM-190381. View

10.

Kim M, Carroll W . Autoregulation of the N-myc gene is operative in neuroblastoma and involves histone deacetylase 2. Cancer. 2004; 101(9):2106-15. DOI: 10.1002/cncr.20626. View

11.

Fan Z, Cui H, Xu X, Lin Z, Zhang X, Kang L . MiR-125a suppresses tumor growth, invasion and metastasis in cervical cancer by targeting STAT3. Oncotarget. 2015; 6(28):25266-80. PMC: 4694830. DOI: 10.18632/oncotarget.4457. View

12.

Shan W, Jiang Y, Yu H, Huang Q, Liu L, Guo X . HDAC2 overexpression correlates with aggressive clinicopathological features and DNA-damage response pathway of breast cancer. Am J Cancer Res. 2017; 7(5):1213-1226. PMC: 5446485. View

13.

Liu D, Tang X, Huang Z, Wen J, Zhou Y . Histone deacetylase HDAC2 regulates microRNA-125a expression in neuroblastoma. Brain Behav. 2022; 12(2):e2401. PMC: 8865159. DOI: 10.1002/brb3.2401. View

14.

Yuan J, Xiao G, Peng G, Liu D, Wang Z, Liao Y . MiRNA-125a-5p inhibits glioblastoma cell proliferation and promotes cell differentiation by targeting TAZ. Biochem Biophys Res Commun. 2014; 457(2):171-6. DOI: 10.1016/j.bbrc.2014.12.078. View

15.

Vogelstein B, Papadopoulos N, Velculescu V, Zhou S, Diaz Jr L, Kinzler K . Cancer genome landscapes. Science. 2013; 339(6127):1546-58. PMC: 3749880. DOI: 10.1126/science.1235122. View

16.

Branca J, Morucci G, Becatti M, Carrino D, Ghelardini C, Gulisano M . Cannabidiol Protects Dopaminergic Neuronal Cells from Cadmium. Int J Environ Res Public Health. 2019; 16(22). PMC: 6888634. DOI: 10.3390/ijerph16224420. View

17.

Lodrini M, Oehme I, Schroeder C, Milde T, Schier M, Kopp-Schneider A . MYCN and HDAC2 cooperate to repress miR-183 signaling in neuroblastoma. Nucleic Acids Res. 2013; 41(12):6018-33. PMC: 3695529. DOI: 10.1093/nar/gkt346. View

18.

Zafar A, Wang W, Liu G, Wang X, Xian W, McKeon F . Molecular targeting therapies for neuroblastoma: Progress and challenges. Med Res Rev. 2020; 41(2):961-1021. PMC: 7906923. DOI: 10.1002/med.21750. View

19.

Louis C, Shohet J . Neuroblastoma: molecular pathogenesis and therapy. Annu Rev Med. 2014; 66:49-63. PMC: 4418018. DOI: 10.1146/annurev-med-011514-023121. View

20.

Tong Z, Liu N, Lin L, Guo X, Yang D, Zhang Q . miR-125a-5p inhibits cell proliferation and induces apoptosis in colon cancer via targeting BCL2, BCL2L12 and MCL1. Biomed Pharmacother. 2015; 75:129-36. DOI: 10.1016/j.biopha.2015.07.036. View