Klf5 acetylation remodels tumor microenvironment to constrain PTEN-deficient prostate tumor growth
CANCER RESEARCH(2024)
Abstract
Abstract Prostate cancer is the most common cancer and the second leading cause of cancer-related death in men in the United States. PTEN deficiency is prevalent in patients with prostate cancer. As a tumor suppressor, PTEN is mutated in approximately 20% of primary prostate cancers, and up to 50% of metastatic castration resistant prostate cancer. PTEN inactivation results in high-grade adenocarcinoma with a long latency. The limited tumor progression induced by PTEN deficiency suggests that additional molecular events are activated to constrain tumor progression, and second hits are required. Understanding these secondary genetic hits will provide the rationale for combined therapies in prostate cancer treatment. In this study, we employed a unique genetically knockin mouse model and found that PTEN deficiency induces a KLF5 K369 acetylation-dependent barrier that attenuates FGFR1 signaling and constrains prostate tumor growth. More importantly, we discovered novel microenvironmental crosstalk between prostate cancer cells and cancer associated fibroblasts (CAFs). As suggested by RNA-seq and bioinformatic analyses and further validated by molecular and cellular experiments, we found that interruption of KLF5 acetylation in cancer cells stimulates CAFs to release FGF9 via TNF-α, and FGF9 activating FGFR1 signaling in cancer cells. In addition to this paracrine crosstalk, deacetylated KLF5 induces CX3CR1 and facilitates FGFR1 activation. Our findings provide a proof of concept for posttranslational modifications as essential molecular events induced by PTEN inactivation to stall prostate cancer progression and demonstrate KLF5 acetylation as a key component in a negative feedback loop by which FGFR1 was suppressed by AKT activation. This study reveals a paracrine reciprocal communication between cancer cells and fibroblasts and provides a clinical rationale for combined therapies using FGFR1 inhibitors (or CX3CR1 inhibitors) and p-AKT inhibitors in PTEN-deficient prostate cancer. Citation Format: Baotong Zhang, Mingcheng Liu, Fengyi Mai, Siyuan Xia, Jin-Tang Dong. Klf5 acetylation remodels tumor microenvironment to constrain PTEN-deficient prostate tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB319.
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