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 7

Klf5 deacetylation enhances FGF/TNF signaling crosstalk between iCAFs and prostate cancer cells.

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Klf5 deacetylation enhances FGF/TNF signaling crosstalk between iCAFs an...
(A) UMAP visualization of the annotated clusters of Krt4+ luminal cell and fibroblast subsets in scRNA-Seq (n = 35,343 cells). Fibroblasts were further divided into iCAFs, MyCAFs, and undefined fibroblasts (other fibroblasts) on the basis of their representative marker genes. (B) Enhanced strength of interactions between iCAFs and Krt4+ luminal cells after Klf5 deacetylation. (C and D) The communication probability of FGF (C) and TNF (D) signaling between Krt4+ luminal cells and different fibroblast subsets was calculated by CellChat and shown as heatmaps. (E) CAFs were ordered along pseudotime trajectories by Monocle2, and cell types and relative Fgf9 expression levels are shown.