DNMT1 expression partially dictates 5-Azacytidine sensitivity and correlates with RAS/MEK/ERK activity in gastric cancer cells

Abstract

ABSTRACT Though DNMTs inhibitors were widely used in myelodysplastic syndrome and leukaemia, their application in solid tumours has been limited by low response rate and lack of optimal combination strategies. In gastric cancer (GC), the therapeutic implication of KRAS mutation or MEK/ERK activation for combinational use of DNMTs inhibitors with MEK/ERK inhibitors remains elusive. In this study, stable knockdown of DNMT1 expression by lentiviral transfection led to decreased sensitivity of GC cells to 5-Azacytidine. KRAS knockdown in KRAS mutant GC cells or the MEK/ERK activation by EGF stimulation in GC cells increased DNMT1 expression, while inhibition of MEK/ERK activity by Selumetinib led to decreased DNMT1 expression. 5-Azacytidine treatment, which led to dramatic decline of DNMTs protein levels and increased activity of MEK/ERK pathway, altered the activity of MEK/ERK inhibitor Selumetinib on GC cells. Both RAS-dependent gene expression signature and expression levels of multiple MEK/ERK-dependent genes were correlated with DNMT1 expression in TCGA stomach cancer samples. In conclusion, DNMT1 expression partially dictates 5-Azacytidine sensitivity and correlates with RAS/MEK/ERK activity in GC cells. Combining DNMTs inhibitor with MEK/ERK inhibitor might be a promising strategy for patients with GC.