Faculty, Staff and Student Publications

Language

English

Publication Date

5-20-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-59381-2

PMID

40394007

PMCID

PMC12092585

PubMedCentral® Posted Date

5-20-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Bone metastasis is a major cause of cancer death; however, the epigenetic determinants driving this process remain elusive. Here, we report that histone methyltransferase ASH1L is genetically amplified and is required for bone metastasis in men with prostate cancer. ASH1L rewires histone methylations and cooperates with HIF-1α to induce pro-metastatic transcriptome in invading cancer cells, resulting in monocyte differentiation into lipid-associated macrophage (LA-TAM) and enhancing their pro-tumoral phenotype in the metastatic bone niche. We identified IGF-2 as a direct target of ASH1L/HIF-1α and mediates LA-TAMs' differentiation and phenotypic changes by reprogramming oxidative phosphorylation. Pharmacologic inhibition of the ASH1L-HIF-1α-macrophages axis elicits robust anti-metastasis responses in preclinical models. Our study demonstrates epigenetic alterations in cancer cells reprogram metabolism and features of myeloid components, facilitating metastatic outgrowth. It establishes ASH1L as an epigenetic driver priming metastasis and macrophage plasticity in the bone niche, providing a bona fide therapeutic target in metastatic malignancies.

Keywords

Humans, Histone-Lysine N-Methyltransferase, Bone Neoplasms, Male, Macrophages, Animals, Mice, Prostatic Neoplasms, DNA-Binding Proteins, Cell Line, Tumor, Cell Differentiation, Hypoxia-Inducible Factor 1, alpha Subunit, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Oxidative Phosphorylation, Cellular Reprogramming, Metabolic Reprogramming

Published Open-Access

yes

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