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抑制 KLF5 乙酰化作用通过重编程癌相关成纤维细胞促进了 PTEN 缺失型前列腺癌的进展。

Interruption of KLF5 acetylation promotes PTEN-deficient prostate cancer progression by reprogramming cancer-associated fibroblasts.

机构信息

Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China.

Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

出版信息

J Clin Invest. 2024 May 23;134(14):e175949. doi: 10.1172/JCI175949.

DOI:10.1172/JCI175949
PMID:38781024
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11245161/
Abstract

Inactivation of phosphatase and tensin homolog (PTEN) is prevalent in human prostate cancer and causes high-grade adenocarcinoma with a long latency. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor progression, but it remains elusive whether and how PTEN-deficient prostate cancers reprogram CAFs to overcome the barriers for tumor progression. Here, we report that PTEN deficiency induced Krüppel-like factor 5 (KLF5) acetylation and that interruption of KLF5 acetylation orchestrated intricate interactions between cancer cells and CAFs that enhance FGF receptor 1 (FGFR1) signaling and promote tumor growth. Deacetylated KLF5 promoted tumor cells to secrete TNF-α, which stimulated inflammatory CAFs to release FGF9. CX3CR1 inhibition blocked FGFR1 activation triggered by FGF9 and sensitized PTEN-deficient prostate cancer to the AKT inhibitor capivasertib. This study reveals the role of KLF5 acetylation in reprogramming CAFs and provides a rationale for combined therapies using inhibitors of AKT and CX3CR1.

摘要

磷酸酶和张力蛋白同源物（PTEN）的失活在人类前列腺癌中很常见，导致潜伏时间长的高级别腺癌。癌相关成纤维细胞（CAFs）在肿瘤进展中起着关键作用，但仍然不清楚 PTEN 缺陷型前列腺癌是否以及如何重新编程 CAFs 以克服肿瘤进展的障碍。在这里，我们报告说，PTEN 缺陷诱导了 Krüppel 样因子 5（KLF5）乙酰化，并且中断 KLF5 乙酰化协调了癌细胞和 CAFs 之间的复杂相互作用，增强了成纤维细胞生长因子受体 1（FGFR1）信号传导并促进肿瘤生长。去乙酰化的 KLF5 促使肿瘤细胞分泌 TNF-α，刺激炎性 CAFs 释放 FGF9。CX3CR1 抑制阻断了 FGF9 触发的 FGFR1 激活，并使 PTEN 缺陷型前列腺癌对 AKT 抑制剂 capivasertib 敏感。这项研究揭示了 KLF5 乙酰化在重新编程 CAFs 中的作用，并为使用 AKT 和 CX3CR1 抑制剂的联合治疗提供了依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/22859fb9458b/jci-134-175949-g062.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/5f67b2a34d12/jci-134-175949-g054.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/b60ae78f517a/jci-134-175949-g055.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/860bad7cb9b8/jci-134-175949-g056.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/f4fe380b667c/jci-134-175949-g057.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/853977077e53/jci-134-175949-g058.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/3115129c3bfe/jci-134-175949-g059.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/9d0b15e86b7b/jci-134-175949-g060.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/392318efc85f/jci-134-175949-g061.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/22859fb9458b/jci-134-175949-g062.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/5f67b2a34d12/jci-134-175949-g054.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/b60ae78f517a/jci-134-175949-g055.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/860bad7cb9b8/jci-134-175949-g056.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/f4fe380b667c/jci-134-175949-g057.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/853977077e53/jci-134-175949-g058.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/3115129c3bfe/jci-134-175949-g059.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/9d0b15e86b7b/jci-134-175949-g060.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/392318efc85f/jci-134-175949-g061.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4c4/11245161/22859fb9458b/jci-134-175949-g062.jpg

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