Acetylation of KLF5 maintains EMT and tumorigenicity to cause chemoresistant bone metastasis in prostate cancer

Baotong Zhang, Yixiang Li, Qiao Wu, Lin Xie, Benjamin Barwick, Changying Fu, Xin Li, Daqing Wu, Siyuan Xia, Jing Chen, Wei Ping Qian, Lily Yang, Adeboye O. Osunkoya, Lawrence Boise, Paula M. Vertino, Yichao Zhao, Menglin Li, Hsiao-Rong Chen, Jeanne Kowalski, Omer Kucuk, Wei Zhou and Jin-Tang Dong ()
Additional contact information
Baotong Zhang: Emory University School of Medicine
Yixiang Li: Emory University School of Medicine
Qiao Wu: Nankai University College of Life Sciences
Lin Xie: Emory University School of Medicine
Benjamin Barwick: Emory University School of Medicine
Changying Fu: Nankai University College of Life Sciences
Xin Li: Augusta University
Daqing Wu: Augusta University
Siyuan Xia: Emory University School of Medicine
Jing Chen: Emory University School of Medicine
Wei Ping Qian: Winship Cancer Institute, Emory University
Lily Yang: Winship Cancer Institute, Emory University
Adeboye O. Osunkoya: Winship Cancer Institute, Emory University
Lawrence Boise: Emory University School of Medicine
Paula M. Vertino: Winship Cancer Institute, Emory University
Yichao Zhao: Emory University School of Medicine
Menglin Li: Emory University School of Medicine
Hsiao-Rong Chen: Emory University
Jeanne Kowalski: Emory University
Omer Kucuk: Emory University School of Medicine
Wei Zhou: Emory University School of Medicine
Jin-Tang Dong: Emory University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-21

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21976-w

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