PTEN inactivation 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. Herein, we report that PTEN deficiency induces KLF5 acetylation; and interruption of KLF5 acetylation orchestrates intricate interactions between cancer cells and CAFs that enhance FGFR1 signaling and promote tumor growth. Deacetylated KLF5 promotes tumor cells to secrete TNF-α, which stimulates inflammatory CAFs to release FGF9. CX3CR1 inhibition blocks FGFR1 activation triggered by FGF9 and sensitizes PTEN-deficient prostate cancer to AKT inhibitor capivasertib. This study reveals the role of KLF5 acetylation in reprogramming CAFs and provides a rational for combined therapies using inhibitors of AKT and CX3CR1.
The Journal of clinical investigation. 2024 May 23 [Epub ahead of print]
Baotong Zhang, Mingcheng Liu, Fengyi Mai, Xiawei Li, Wenzhou Wang, Qingqing Huang, Xiancai Du, Weijian Ding, Yixiang Li, Benjamin Barwick, Jianping Ni, Adeboye Osunkoya, Yuanli Chen, Wei Zhou, Siyuan Xia, Jin-Tang Dong
Department of Human Cell Biology and Genetics, Southern University of Science and Technology, Shenzhen, China., Department of Hematology and Medical Oncology, Radiation-Diagnostic/Oncology School of Medicine, Emory University, Atlanta, United States of America., Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, United States of America., Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, United States of America., Pharmacological Sciences, Hefei University of Technology, Hefei, China.