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• The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients 

Published in Volume 120, Issue 2 (February 1, 2010) J Clin Invest. 2010;120(2):521–532. doi:10.1172/JCI40706.
Jump to full article: Journal of Clinical Investigation, 2010-02-01

Intro:

DNMT1 overexpression strongly correlates with smoking status and poor prognosis of lung cancer patients. . . .

NNK increases DNMT1 protein expression and activity. . . .

NNK prolongs DNMT1 protein stability through AKT signaling, which is associated with the ubiquitin-proteosome system. . . .

NNK activates AKT, then inhibits GSK3β/β-transducin repeat–containing protein–mediated protein degradation, leading to DNMT1 protein accumulation. . . .

NNK treatment enhances AKT downstream proteins, promotes hnRNP-U/βTrCP translocation to the cytoplasm, and induces DNMT1 accumulation in the nucleus . . .

NNK induces DNMT1, p-AKTser473, p-GSK3βser9, cytoplasmic hnRNP-U, and cytoplasmic βTrCP protein expression level in mouse lung adenoma tissues. . . .

DNMT1 and βTrCP interaction is disrupted in lung tumor tissue of patients who smoked.

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