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 NFκB signaling, and NFκB activates its downstream effector, DNA methylation machinery. Indeed,
nucleolin overexpression increased NFκB phosphorylation and upregulated DNMT1 that is followed by DNA demethylation; by contrast,
nucleolin dysfunction dephosphorylated NFκB and abrogated DNMT1 expression, which resulted in decreased global DNA methylation, restored p15INK4B expression and
DNA hypomethylation on p15INK4B promoter. Notably, NFκB inactivation diminished, whereas NFκB 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-NFκB-DNMT1 axis as a new molecular pathway underlying AML leukemogenesis.