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 9

Higher expression levels of FGF9 and CX3CR1 correlate with the activation of FGFR1 signaling in human prostate cancer.

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Higher expression levels of FGF9 and CX3CR1 correlate with the activatio...
(A) Correlation of FGF9 and CX3CR1 with FGFR1 activation in prostate cancer samples from TCGA database. ssGSEA was used to identify FGFR1 activation for 499 cancer samples using 3 different REACTOME gene sets. The gene expression levels of FGF9 and CX3CR1 were normalized into a z score. (B) Representative images of IHC staining of FGF9, CX3CR1, and p-FRS2 in p-AKT+ prostate cancer samples. Scale bar: 50 μm. (C–E) In p-AKT+ tumors, the expression levels of CX3CR1 and p-FRS2 were positively correlated in FGF9+ conditions. All, all p-AKT+ tumors (C); FGF9+, FGF9+/p-AKT+ tumors (D); FGF9–, FGF9–/p-AKT+ tumors (E). (F–H) In p-AKT+ tumors, the expression levels of FGF9 and p-FRS2 are positively correlated in the condition of CX3CR1hi. All, all p-AKT+ tumors (F); CX3CR1hi, CX3CR1hi/p-AKT+ tumors (G); CX3CR1lo, CX3CR1lo/p-AKT+ tumors (H). The definition of the expression levels of p-AKT, FGF9, and CX3CR1 refer to Supplemental Table 1. *P < 0.05, by Pearson analyses (C–H). (I) Schematic depicting how PTEN deficiency–induced KLF5 acetylation constrains prostate cancer progression by attenuating FGFR1 activation via CAF reprogramming. This illustration was generated using BioRender (publication agreement no. CZ26N14CEQ).