Acetylation of KLF5 maintains EMT and tumorigenicity to cause chemoresistant bone metastasis in prostate cancer
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 17, 2021
- Source ID
- 10.1038/s41467-021-21976-w
Entities
People
- Adeboye O Osunkoya
- Baotong Zhang
- Benjamin G Barwick
- Changying Fu
- Daqing Wu
- Hsiao-rong Chen
- Jeanne Kowalski
- Jin-Tang Dong
- Jing Chen
- Lawrence H Boise
- Lily Yang
- Lin Xie
- Menglin Li
- Omer Kucuk
- Paula Vertino
- Qiao Wu
- Siyuan Xia
- Wei Ping Qian
- Wei Zhou
- Xin Li
- Yichao Zhao
- Yixiang Li
Organizations
- National Cancer Institute
- United States Department of Defense