Interruption of KLF5 acetylation promotes PTEN-deficient prostate cancer progression by reprogramming cancer-associated fibroblasts
Baotong Zhang, … , Siyuan Xia, Jin-Tang Dong
Baotong Zhang, … , Siyuan Xia, Jin-Tang Dong
Published May 23, 2024
Citation Information: J Clin Invest. 2024;134(14):e175949. https://doi.org/10.1172/JCI175949.
View: Text | PDF
Research Article Oncology

Interruption of KLF5 acetylation promotes PTEN-deficient prostate cancer progression by reprogramming cancer-associated fibroblasts

Abstract

Inactivation of phosphatase and tensin homolog (PTEN) is prevalent in human prostate cancer and causes high-grade adenocarcinoma with a long latency. 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. Here, we report that PTEN deficiency induced Krüppel-like factor 5 (KLF5) acetylation and that interruption of KLF5 acetylation orchestrated intricate interactions between cancer cells and CAFs that enhance FGF receptor 1 (FGFR1) signaling and promote tumor growth. Deacetylated KLF5 promoted tumor cells to secrete TNF-α, which stimulated inflammatory CAFs to release FGF9. CX3CR1 inhibition blocked FGFR1 activation triggered by FGF9 and sensitized PTEN-deficient prostate cancer to the AKT inhibitor capivasertib. This study reveals the role of KLF5 acetylation in reprogramming CAFs and provides a rationale for combined therapies using inhibitors of AKT and CX3CR1.

Authors

Baotong Zhang, Mingcheng Liu, Fengyi Mai, Xiawei Li, Wenzhou Wang, Qingqing Huang, Xiancai Du, Weijian Ding, Yixiang Li, Benjamin G. Barwick, Jianping Jenny Ni, Adeboye O. Osunkoya, Yuanli Chen, Wei Zhou, Siyuan Xia, Jin-Tang Dong

×

Figure 5

Increased Fgf9 in CAFs contributes to hyperactivated FGFR1 signaling in Klf5KR tumor cells with the Klf5KR knockin.

Options: View larger image (or click on image) Download as PowerPoint
Increased Fgf9 in CAFs contributes to hyperactivated FGFR1 signaling in ...
(A) CM containing CAFs from PBCre Pten–/– Klf5KR/KR mice were more potent in activating FGFR1 in DU 145 and PC-3 prostate cancer cells, as indicated by the expression levels of p-ERKThr202/Tyr204 and p-FRS2Tyr436 detected by Western blotting. (B and C) Fgf9 expression levels in Pten-null mouse prostates with the indicated Klf5 statuses, as measured by IF staining (B) and IHC staining (C). The mice used were 16 weeks of age. Scale bars: 50 μm. (D and E) Fgf9 mRNA and protein expression levels in isolated CAFs from mice of the indicated genotypes, as determined by real-time qPCR (D) and ELISA (E). WT is PBCre Pten–/– Klf5WT/WT and KR is PBCre Pten–/– Klf5KR/KR. ***P < 0.001, by 2-way ANOVA (C–E). Data are shown as the mean ± SEM. (F) FGF9-induced FGFR1 activation was suppressed by the FGFR1 inhibitor AZD4547. (G) FGF9 was more potent in activating FGFR1 signaling, as indicated by the expression levels of p-ERKThr202/Tyr204 and p-FRS2Tyr436 by Western blotting. In F and G, DU 145 cells were treated as indicated in the figures.