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.
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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

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Figure 6

Interruption of Klf5 acetylation upregulates TNF-α in Pten-null tumor cells to induce FGF9 secretion in CAFs.

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Interruption of Klf5 acetylation upregulates TNF-α in Pten-null tumor ce...
(A and B) Expression levels of Fgf9 mRNA and protein were higher in isolated CAFs when cocultured with 2 prostate cancer cell lines PC-3 and DU 145 with the KLF5KR mutant, as detected by real-time qPCR (A) and ELISA (B). (C) Heatmap showing expression of activators and suppressors of FGF9 as reviewed from 617 publications. Red and green indicate the genes upregulated and downregulated by the Klf5KR mutant. (D) The top ligands that signal fibroblasts from Krt4+ luminal cells were calculated by NicheNet, and their expression levels in Krt4+ luminal cells are shown as violin plots. (E) Plots of Tnf expression as detected by RNA-Seq. W/W, PBCre Pten–/– Klf5WT/WT; KR/W, PBCre Pten–/– Klf5WT/KR; KR/KR, PBCre Pten–/– Klf5KR/KR. (F) IHC staining for Tnf-α in mouse prostate tumors of the indicated genotypes. Scale bar: 50 μm. (G) The expression levels of TNF-α mRNA and protein were higher in DU 145 cells expressing the KLF5KR mutant, as indicated by real-time qPCR (left) and ELISA (right). DU 145 cells were cultured under the indicated conditions. CAFs from Pten-deficient mouse prostate tumors were used to produce CM and cocultured with DU 145 cells. (H) TNF-α induced Fgf9 expression levels in CAFs, as indicated by real-time qPCR (left) and ELISA (right). (I) Blockage of TNF-α signaling by the neutralizing antibodies against TNF-α (5 ng/mL), TNFR1 (20 μg/mL), or TNFR2 (5 ng/mL) suppressed Fgf9 expression that was induced in CAFs by expression of the KLF5KR mutant in DU 145 cells. Data are shown as the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed Student’s t test (A, B, E, and G–I) and 2-way ANOVA (F).