Lysine 69 deacetylation of NFIC drives autophagy-induced epithelial–mesenchymal transition and chemoresistance in glioblastoma

Abstract Acquired temozolomide (TMZ) resistance is a major obstacle in improving glioblastoma multiforme (GBM) treatment. Accumulating evidence has indicated that autophagy has dual effects on the regulation of chemoresistance. In our previous study, we reported that autophagic inducers can upregulate the E3 ligase HERC3 and then mediate TMZ resistance by activating the HERC3/SMAD7/TGF-β pathway. However, the underlying mechanism within the increasing expression of HERC3 induced by autophagy is still unknown. Herein, we show that autophagy promotes the deacetylation of nuclear factor I C (NFIC) at lysine 69, which induces the transcriptional activation of forkhead box protein K1 (FOXK1) and thus promotes HERC3 dependent epithelial‒mesenchymal transition (EMT). The dynamic equilibrium of NFIC K69Ac is controlled by the acetyltransferase P300 and the deacetylase HDAC6. Pe-k69, a cell-penetrating peptide, can specifically block NFIC K69 deacetylation and sensitise GBM cells to TMZ. Our study reveals an acetylation-dependent regulatory mechanism, which may provide mechanistic clues for targeting NFIC to overcome GBM chemoresistance.