Interuption of Klf5 acetylaiton at K358 affects gene expression profiles in Pten deficient mouse prostates
Cancer associated fibroblasts (CAFs) play a pivotal role in tumor progression, but it remains elusive whether and how PTEN-deficient prostate cancers reprogram CAFs to overcome the barriers for tumor progression. Herein, we report that PTEN deficiency induces KLF5 acetylation; and interruption of KLF5 acetylation orchestrates intricate interactions between cancer cells and CAFs that enhance FGFR1 signaling and promote tumor growth. Deacetylated KLF5 promotes tumor cells to secrete TNF-a, which stimulates inflammatory CAFs to release FGF9. CX3CR1 inhibition blocks FGFR1 activation triggered by FGF9 and sensitizes PTEN-deficient prostate cancer to AKT inhibitor capivasertib. Overall design: Differential gene expression caused by Klf5-K358R (KR) knockin in Pten-loss mouse prostates were determined by RNA-seq in anterior prostates (AP) and dorsal prostates (DP). The prostates were dissected from 16-week mice with the genotypes of PB-Cre::Pten F/F::Klf5 W/W (WW); PB-Cre::Pten F/F::Klf5 KR/W (KRW); PB-Cre::Pten F/F::Klf5 KR/KR (KRKR).