DNMT3B has not previously been connected with the biology underlying the risk of nicotine dependence or any other SUD. However, there is evidence that in vitro cigarette smoke exposure leads to increased DNMT3B expression in human respiratory epithelial cells, and DNMT3B overexpression results in downstream hypermethylation that has been widely implicated in lung cancer.53 Given this indication, DNMT inhibition has been an active area of research for cancer treatment; two inhibitor agents are currently approved by the US Food and Drug Administration (decitabine, which shows high affinity for DNMT3A/3B over DNMT1,54 and azacytidine), and at least one other promising agent (zebularine) awaits clinical trial testing.55 With the DNMT3B variant discovery for nicotine dependence, DNMT3B inhibition may merit future study for smoking cessation treatment.
