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

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Figure 8

Klf5 deacetylation upregulates CX3CR1 to enhance FGFR1 signaling activity, and blocking CX3CR1 sensitizes tumor cells to AKT inhibition.

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Klf5 deacetylation upregulates CX3CR1 to enhance FGFR1 signaling activit...
(A and B) The expression levels of Cx3cr1 were higher in PBCre Pten–/– Klf5KR/KR prostate tumors, as indicated by RNA-Seq (A) and IHC staining (B). W/W, PBCre Pten–/– Klf5WT/WT; KR/W, PBCre Pten–/– Klf5WT/KR; KR/KR, PBCre Pten–/– Klf5KR/KR. Scale bar: 50 μm. (C) Expression of CX3CR1 mRNA in DU 145 prostate cancer cells with KLF5WT (KLF5) or KLF5KR (KR) by real-time qPCR. (D) DU 145 cells expressing KLF5WT (KLF5) and KLF5KR (KR) were treated with FGF9 (50 ng/mL) for 5 minutes. FGFR1 downstream p-ERKThr202/Tyr204 and p-FRS2Tyr436 were detected by Western blotting. G2 and G3 are 2 shRNAs of CX3CR1. shCon, control shRNA. (E) Inhibitors of CX3CR1 selectively suppressed the organoid formation of mouse prostate cancer cells with the Klf5KR mutant in the context of Pten deficiency. AZD8797 (50 nM) and JMS-17-2 (1 nM) are 2 different CX3XR1 inhibitors. (F–H) PTEN-deficient PDXs (The Jackson Laboratory, TM00298) on NSG mice were treated daily with the AKT inhibitor capivasertib and/or the CX3CR1 inhibitor JMS-17-2 as indicated. JMS-17-2 sensitized the effects of capivasertib on PDX growth, as indicated by the tumor volumes at different time points (F), tumor weights (G), and images (H) at excision. (I) The expression levels of Ac-KLF5, p-FRS2, and Ki67 were evaluated by IHC staining and quantitative analysis. Scale bars: 50 µm. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed Student’s t test (A, C, E, and G) and 2-way ANOVA (B, F and I).