Acetylation of KLF5 maintains EMT and tumorigenicity to cause chemoresistant bone metastasis in prostate cancer
Baotong Zhang, Yixiang Li, Qiao Wu, Lin Xie, Benjamin G. Barwick, Changying Fu, Xin Li, Daqing Wu, Siyuan Xia, Jing Chen, Wei Qian, Lily Yang, Adeboye O. Osunkoya, Lawrence Boise, Paula M. Vertino, Yichao Zhao, Menglin Li, Hsiao-Rong Chen, Jeanne Kowalski, Ömer Küçük, Wei Zhou, Jin‐Tang Dong
Abstract
Advanced prostate cancer (PCa) often develops bone metastasis, for which therapies are very limited and the underlying mechanisms are poorly understood. We report that bone-borne TGF-β induces the acetylation of transcription factor KLF5 in PCa bone metastases, and acetylated KLF5 (Ac-KLF5) causes osteoclastogenesis and bone metastatic lesions by activating CXCR4, which leads to IL-11 secretion, and stimulating SHH/IL-6 paracrine signaling. While essential for maintaining the mesenchymal phenotype and tumorigenicity, Ac-KLF5 also causes resistance to docetaxel in tumors and bone metastases, which is overcome by targeting CXCR4 with FDA-approved plerixafor. Establishing a mechanism for bone metastasis and chemoresistance in PCa, these findings provide a rationale for treating chemoresistant bone metastasis of PCa with inhibitors of Ac-KLF5/CXCR4 signaling.