Inhibition of PSF Activity Overcomes Resistance to Treatment in Cancers Harboring Mutant p53

Abstract

Mutations in the TP53 tumor suppressor genes are prevalent in aggressive cancers. Pharmacologic reactivation of dysfunctional p53 due to mutations is a promising strategy for treating such cancers. Recently, a multifunctional proline- and glutamine-rich protein, polypyrimidine tract-binding protein-associated splicing factor (PSF), was identified as a key driver of aggressive cancers. PSF promotes the expression of numerous oncogenes by modulating epigenetic and splicing mechanisms. We previously screened a small-molecule library and discovered compound No. 10-3 as a potent PSF inhibitor. Here, we report the discovery of a No. 10-3 analog, 7,8-dimethoxy-4-(4-methoxy-phenyl)-chromen-2-one (C-30), as a potent PSF inhibitor. Compared with No. 10-3, C-30 treatment specifically suppressed the growth and induced apoptosis of mutant p53-bearing and therapy-resistant cancer cells. Interestingly, C-30 activated a set of p53-regulated genes in therapy-resistant cancer cells. A comprehensive analysis of PSF and p53-binding regions demonstrated a higher level of PSF-binding potential in mutant p53-expressing cancer cells around genomic regions identified as p53-binding peaks in p53 wild-type cancer cells. Treatment of mutant p53-expressing cancer cells with C-30 decreases PSF binding around these sites, leading to activated histone acetylation. We further demonstrated that C-30 impaired tumor growth and increased the expression of p53 target genes in vivo. These results suggested that C-30 produces tumor-suppressive effects similar to the functional reactivation of p53, providing a rationale for the inhibition of PSF activity as a promising therapy against treatment-resistant cancer.