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Author Notes:

Jin-Tang Dong, Email: dongjt@sustech.edu.cn

B.Z. designed and performed most experiments, analyzed the data, and wrote the manuscript; Q.W. and C.F. performed RNA-Seq and ChIP-Seq experiments; Y.L., B.B., L.B., P.M.V., H.R.C., and J.K. performed bioinformatic analyses; L.X., X.L., D.W., W-P.Q., L.Y., and S.X. performed some of the animal experiments; J.C., O.K., and W.Z. helped with some experimental designs; A.O.O. conducted pathological analyses; Y.Z. and M.L. performed some experiments; and J.D. conceived the project, designed and supervised the study, analyzed the data, provided overall guidance, and revised and finalized the manuscript.

We thank Dr. Anthea Hammond of Emory University for editing the manuscript. We thank Dr. Dezhi Wang at the Pathology Core Research Lab in the Department of Pathology of University of Alabama at Birmingham for processing bone tissues. We thank Ms. Lingwei Xiang from ICF for statistical input in data analysis.

The authors declare no competing interests.

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Research Funding:

This work was supported by grant W81XWH-18-1-0526 from Department of Defense Prostate Cancer Research Program, grant R01CA171189 from the National Institutes of Health, and grant 81130044 from the National Natural Science Foundation of China. The research reported in this publication was supported in part by the Integrated Cellular Imaging Core Facility, the Research Pathology Core Laboratory, and the Emory Integrated Genomics Core of Emory University Winship Cancer Institute under NIH/NCI award number P30CA138292. The tissue microarray of bone metastasis samples from PCa patients in this work is from the Prostate Cancer Biorepository Network (PCBN) supported by the Department of Defense Prostate Cancer Research Program Awards W81XWH-18-2-0013, W81XWH-18-2-0015, W81XWH-18-2-0016, W81XWH-18-2-0017, W81XWH-18-2-0018, and W81XWH-18-2-0019.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics

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

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Journal Title:

NATURE COMMUNICATIONS

Volume:

Volume 12, Number 1

Publisher:

, Pages 1714-1714

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© The Author(s) 2021

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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