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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Acetylation
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Animals
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Benzylamines / therapeutic use
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Bone Neoplasms / drug therapy
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Bone Neoplasms / genetics
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Bone Neoplasms / metabolism
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Bone Neoplasms / secondary*
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Carcinogenesis*
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Cell Line, Tumor
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Cyclams / therapeutic use
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Docetaxel / therapeutic use
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Epithelial-Mesenchymal Transition*
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Humans
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Interleukin-11 / genetics
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Interleukin-11 / metabolism
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism*
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Male
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Mice
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Mutation
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Osteogenesis
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Prostatic Neoplasms, Castration-Resistant / drug therapy
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Prostatic Neoplasms, Castration-Resistant / genetics
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Prostatic Neoplasms, Castration-Resistant / metabolism
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Prostatic Neoplasms, Castration-Resistant / pathology*
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Receptors, CXCR4 / antagonists & inhibitors
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Receptors, CXCR4 / genetics
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Receptors, CXCR4 / metabolism
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Signal Transduction
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Transforming Growth Factor beta / metabolism
Substances
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Benzylamines
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CXCR4 protein, human
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Cyclams
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Interleukin-11
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KLF5 protein, human
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Kruppel-Like Transcription Factors
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Receptors, CXCR4
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Transforming Growth Factor beta
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Docetaxel
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plerixafor