Epigenetic silencing of the tumor suppressor microRNA Hsa-miR-124a regulates CDK6 expression and confers a poor prognosis in acute lymphoblastic leukemia
- PMID: 19435910
- DOI: 10.1158/0008-5472.CAN-08-4025
Epigenetic silencing of the tumor suppressor microRNA Hsa-miR-124a regulates CDK6 expression and confers a poor prognosis in acute lymphoblastic leukemia
Abstract
Whereas transcriptional silencing of genes due to epigenetic mechanisms is one of the most important alterations in acute lymphoblastic leukemia (ALL), some recent studies indicate that DNA methylation contributes to down-regulation of miRNAs during tumorigenesis. To explore the epigenetic alterations of miRNAs in ALL, we analyzed the methylation and chromatin status of the miR-124a loci in ALL. Expression of miR-124a was down-regulated in ALL by hypermethylation of the promoter and histone modifications including decreased levels of 3mk4H3 and AcH3 and increased levels of 2mK9H3, 3mK9H3, and 3mK27H3. Epigenetic down-regulation of miR-124a induced an up-regulation of its target, CDK6, and phosphorylation of retinoblastoma (Rb) and contributed to the abnormal proliferation of ALL cells both in vitro and in vivo. Cyclin-dependent kinase 6 (CDK6) inhibition by sodium butyrate or PD-0332991 decreased ALL cell growth in vitro, whereas overexpression of pre-miR124a led to decreased tumorigenicity in a xenogeneic in vivo Rag2(-/-)gammac(-/-) mouse model. The clinical implications of these findings were analyzed in a group of 353 patients diagnosed with ALL. Methylation of hsa-miR-124a was observed in 59% of the patients, which correlated with down-regulation of miR-124a (P < 0.001). Furthermore, hypermethylation of hsa-miR-124a was associated with higher relapse rate (P = 0.001) and mortality rate (P < 0.001), being an independent prognostic factor for disease-free survival (P < 0.001) and overall survival (P = 0.005) in the multivariate analysis. These results provide the grounds for new therapeutic strategies in ALL either targeting the epigenetic regulation of microRNAs and/or directly targeting the CDK6-Rb pathway.
Similar articles
-
[Epigenetic alterations in acute lymphoblastic leukemia].Bol Med Hosp Infant Mex. 2017 Jul-Aug;74(4):243-264. doi: 10.1016/j.bmhimx.2017.02.005. Epub 2017 Jul 15. Bol Med Hosp Infant Mex. 2017. PMID: 29382514 Review. Spanish.
-
Epigenetic regulation of miRNA genes in acute leukemia.Leukemia. 2012 Mar;26(3):395-403. doi: 10.1038/leu.2011.344. Epub 2011 Dec 6. Leukemia. 2012. PMID: 22143672 Review.
-
Deregulation of FGFR1 and CDK6 oncogenic pathways in acute lymphoblastic leukaemia harbouring epigenetic modifications of the MIR9 family.Br J Haematol. 2011 Oct;155(1):73-83. doi: 10.1111/j.1365-2141.2011.08812.x. Epub 2011 Aug 2. Br J Haematol. 2011. PMID: 21810092
-
[Role of miR-124a methylation in patients with gastric cancer].Zhonghua Wei Chang Wai Ke Za Zhi. 2011 Feb;14(2):136-9. Zhonghua Wei Chang Wai Ke Za Zhi. 2011. PMID: 21365509 Chinese.
-
Epigenetic regulation of microRNAs in acute lymphoblastic leukemia.J Clin Oncol. 2009 Mar 10;27(8):1316-22. doi: 10.1200/JCO.2008.19.3441. Epub 2009 Jan 21. J Clin Oncol. 2009. PMID: 19164206
Cited by
-
Liquid biopsy utilizing miRNA in patients with advanced breast cancer treated with cyclin‑dependent kinase 4/6 inhibitors.Oncol Lett. 2024 Feb 28;27(4):181. doi: 10.3892/ol.2024.14314. eCollection 2024 Apr. Oncol Lett. 2024. PMID: 38464342 Free PMC article.
-
A semi-supervised approach for the integration of multi-omics data based on transformer multi-head self-attention mechanism and graph convolutional networks.BMC Genomics. 2024 Jan 22;25(1):86. doi: 10.1186/s12864-024-09985-7. BMC Genomics. 2024. PMID: 38254021 Free PMC article.
-
The Role of miRNAs in Childhood Acute Lymphoblastic Leukemia Relapse and the Associated Molecular Mechanisms.Int J Mol Sci. 2023 Dec 21;25(1):119. doi: 10.3390/ijms25010119. Int J Mol Sci. 2023. PMID: 38203290 Free PMC article. Review.
-
Diagnostic significance of dysregulated miRNAs in T-cell malignancies and their metabolic roles.Front Oncol. 2023 Aug 10;13:1230273. doi: 10.3389/fonc.2023.1230273. eCollection 2023. Front Oncol. 2023. PMID: 37637043 Free PMC article. Review.
-
Can Dietary Actives Affect miRNAs and Alter the Course or Prevent Colorectal Cancer?Int J Mol Sci. 2023 Jun 14;24(12):10142. doi: 10.3390/ijms241210142. Int J Mol Sci. 2023. PMID: 37373289 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical