The histone acetylranseferase h MOF acetylates Nrf 2 and regulates anti‐drug responses in human non‐small cell lung cancer

Background and Purpose The histone acetyltransferase MOF is a member of the MYST family. In mammals, MOF plays critical roles by acetylating histone H 4 at K 16 and non‐histone substrates such as p53. Here we have investigated the role of MOF in human lung cancer and possible new substrates of h MOF . Experimental Approach Samples of human non‐small cell lung cancer ( NSCLC ) were used to correlate MOF with clinicopathological parameters and NF–E2‐related factor 2 ( Nrf 2) downstream genes. 293 T ‐cells were used to study interactions between MOF and Nrf 2, and acetylation of Nrf 2 by MOF . Mouse embryonic fibroblast and A 549 cells were utilized to assess involvement of MOF in antioxidative and anti‐drug responses. A 549 cells were used to analysis the role of MOF in anti‐drug response in vitro and in vivo . Key Results hMOF was overexpressed in human NSCLC tissues and was associated with large tumour size, advanced disease stage and metastasis, and with poor prognosis. h MOF levels were positively correlated with Nrf 2‐downstream genes. MOF /h MOF physically interacted with and acetylated Nrf 2 at L ys 588 . MOF ‐mediated acetylation increased nuclear retention of Nrf 2 and transcription of its downstream genes. Importantly, MOF /h MOF was essential for anti‐oxidative and anti‐drug responses in vitro and regulated tumour growth and drug resistance in vivo in an Nrf 2‐dependent manner. Conclusion and Implications h MOF was overexpressed in human NSCLC and was a predictor of poor survival. h MOF ‐mediated Nrf 2 acetylation and nuclear retention are essential for anti‐oxidative and anti‐drug responses. h MOF may provide a therapeutic target for the treatment of NSCLC .