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

• DOI: 10.1172/jci175949
• Publication Date: 2024-07-14T18:00:36Z
• 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
• Keywords: Male; Mice; Cancer-Associated Fibroblasts; Cell Line, Tumor; PTEN Phosphohydrolase; Kruppel-Like Transcription Factors; Prostatic Neoplasms; Humans; Animals; Acetylation; Cellular Reprogramming; Research Article

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.