| Literature DB >> 33731701 |
Baotong Zhang1,2, Yixiang Li1,2, Qiao Wu3, Lin Xie1,2,4, Benjamin Barwick1,2, Changying Fu3,5, Xin Li6, Daqing Wu6, Siyuan Xia1,2, Jing Chen1,2, Wei Ping Qian2,7, Lily Yang2,7, Adeboye O Osunkoya2,8, Lawrence Boise1,2, Paula M Vertino2,9, Yichao Zhao1,2, Menglin Li1,2, Hsiao-Rong Chen10, Jeanne Kowalski10, Omer Kucuk1,2, Wei Zhou1,2, Jin-Tang Dong11,12,13.
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.Entities:
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Year: 2021 PMID： 33731701 PMCID： PMC7969754 DOI： 10.1038/s41467-021-21976-w
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919