Acetylation of Smad1 promotes tumorigenesis and chemoresistance via competitive attenuation of p300-mediated p53 acetylation in glioblastoma

Abstract Aberrant post-translational modification (PTM) is a key molecular event inciting p53 tumor suppressor function loss or transformation. Here, we report that p53 acetylation, independent of the overall level of p53 expression, predicts improved survival in glioblastoma (GBM). It revealed that acetylation at the C-terminal domain (CTD) reversed tumorigenic gain of function (GOF) of p53 mutants in GBM. An important finding was that acetylation not only strengthened the tumor suppression of wild-type p53, but also reinforced the chemosensitivity of GBM cells with missense mutant p53, as evidenced by attenuated DNA damage repair. Mechanical exploration revealed that the acetylation of p53 in GBM was negatively regulated by Smad1. Smad1 served as an oncoprotein in GBM by promoting tumorigenesis and chemoresistance in a BMP or TGF-β independent manner. It formed a ternary complex with p53 through the MH1 domain and with p300 through the MH2 domain, inhibiting p300-mediated p53 acetylation via competitively binding of the C-terminus of p300. Acetylated Smad1 was identified by p300 at the lysine site 373 (K373). Smad1 acetylation was indispensable due to its transcriptional activity and onco-functions. Collectively, this study highlights that acetylation is critical for p53 and Smad1 functions, and that Smad1 acts as an oncoprotein partially by impairing p53 acetylation in GBM.