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A nucleolin-DNMT1 regulatory axis in acute myeloid leukemogenesis.

ABSTRACT: Nucleolin overexpression and DNA hypermethylation have been implicated in cancer pathogenesis, but whether and how these aberrations cooperate in controlling leukemia cell fate remains elusive. Here, we provide the first mechanistic insights into the role of nucleolin in leukemogenesis through creating a DNA hypermethylation profile in leukemia cells. We found that, in leukemia patients, nucleolin levels are significantly elevated and nucleolin overexpression strongly associates with DNMT upregulation and shorter survival. Enforced nucleolin expression augmented leukemia cell proliferation, whereas nucleolin dysfunction by RNA interference and inhibitory molecule AS1411 blocked leukemia cell clonogenic potential in vitro and impaired tumorigenesis in vivo. Mechanistic investigations showed that nucleolin directly activates NF?B signaling, and NF?B activates its downstream effector, DNA methylation machinery. Indeed, nucleolin overexpression increased NF?B phosphorylation and upregulated DNMT1 that is followed by DNA demethylation; by contrast, nucleolin dysfunction dephosphorylated NF?B and abrogated DNMT1 expression, which resulted in decreased global DNA methylation, restored p15INK4B expression and DNA hypomethylation on p15INK4B promoter. Notably, NF?B inactivation diminished, whereas NF?B overexpression enhanced DNMT1 promoter activity and endogenous DNMT1 expression. Collectively, our studies identify nucleolin as an unconventional epigenetic regulator in leukemia cells and demonstrate nucleolin-NF?B-DNMT1 axis as a new molecular pathway underlying AML leukemogenesis.

SUBMITTER: Shen N

PROVIDER: S-EPMC4170608 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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A nucleolin-DNMT1 regulatory axis in acute myeloid leukemogenesis.

Shen Na N Yan Fei F Pang Jiuxia J Wu Lai-Chu LC Al-Kali Aref A Litzow Mark R MR Liu Shujun S

Oncotarget 20140701 14

Nucleolin overexpression and DNA hypermethylation have been implicated in cancer pathogenesis, but whether and how these aberrations cooperate in controlling leukemia cell fate remains elusive. Here, we provide the first mechanistic insights into the role of nucleolin in leukemogenesis through creating a DNA hypermethylation profile in leukemia cells. We found that, in leukemia patients, nucleolin levels are significantly elevated and nucleolin overexpression strongly associates with DNMT upregu ...[more]

PMID: 25015109

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Project description:Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic malignancies due to sophisticated genetic mutations and epigenetic dysregulation. MicroRNAs (miRNAs), a class of small non-coding RNAs, are important regulators of gene expression in all biological processes, including leukemogenesis. Recently, miR-375 has been reported to be a suppressive miRNA in multiple types of cancers, but its underlying anti-leukemia activity in AML is largely unknown.Quantitative reverse transcriptase PCR (qRT-PCR) was used to measure the expression of miR-375 and HOXB3 in leukemic cells and normal controls. Targets of miR-375 were confirmed by western blot and luciferase assay. Phenotypic effects of miR-375 overexpression and HOXB3 knockdown were assessed using viability (trypan blue exclusion assay), colony formation/replating, as well as tumor xenograft assays in vivo.The expression of miR-375 was substantially decreased in leukemic cell lines and primary AML blasts compared with normal controls, because DNA hypermethylation of precursor-miR-375 (pre-miR-375) promoter was discovered in leukemic cells but not in normal controls. Lower expression of miR-375 predicted poor outcome in AML patients. Furthermore, forced expression of miR-375 not only decreased proliferation and colony formation in leukemic cells but also reduced xenograft tumor size and prolonged the survival time in a leukemia xenograft mouse model. Mechanistically, overexpression of miR-375 reduced HOXB3 expression and repressed the activity of a luciferase reporter through binding 3'-untranslated regions (3'-UTR) of HOXB3 mRNA. Overexpression of HOXB3 partially blocked miR-375-induced arrest of proliferation and reduction of colony number, suggesting that HOXB3 plays an important role in miR-375-induced anti-leukemia activity. Knockdown of HOXB3 by short hairpin RNAs reduced the expression of cell division cycle associated 3 (CDCA3), which decreased cell proliferation. Furthermore, HOXB3 induced DNA methyltransferase 3B (DNMT3B) expression to bind in the pre-miR-375 promoter and enhanced DNA hypermethylation of pre-miR-375, leading to the lower expression of miR-375.Collectively, we have identified a miR-375-HOXB3-CDCA3/DNMT3B regulatory circuitry which contributes to leukemogenesis and suggests a therapeutic strategy of restoring miR-375 expression in AML.

Dataset Information

A nucleolin-DNMT1 regulatory axis in acute myeloid leukemogenesis.

Publications

A nucleolin-DNMT1 regulatory axis in acute myeloid leukemogenesis.

Similar Datasets

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