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Histone Methyltransferase ASH1L Primes Metastases and Metabolic Reprogramming of Macrophages in the Bone Niche (RNA-Seq)

ABSTRACT: Bone metastasis is a major cause of cancer death; however, the epigenetic determinants driving this process remain elusive. Here, we uncover that histone methyltransferase ASH1L is genetically amplified in metastatic diseases and is required for cancer invasiveness and bone metastasis. In invading cancer cells, ASH1L rewires methylations at H3K4 and H3K36 and cooperates with transcriptional factor HIF-1α to induce pro-metastatic transcriptome. Leveraging our newly developed metastasis models and single-cell transcriptomic profiling, we demonstrate that ASH1L in invading cancer cells induces monocyte differentiation into lipid-associated macrophage (LA-TAM) and maintains their pro-tumoral and anti-inflammatory phenotype in the metastatic bone niche. Mechanistic studies reveal that IGF-2 is a direct target of ASH1L and mediates LA-TAMs’ differentiation and phenotypic changes by reprogramming oxidative phosphorylation. In patients with metastatic cancers, ASH1L overexpression is associated with enriched LA-TAMs. As a proof of concept, pharmacologic inhibition of the ASH1L-macrophages axis elicits robust anti-metastasis responses in preclinical models.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269830 | GEO | 2025/03/20

REPOSITORIES: GEO

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Histone Methyltransferase ASH1L Primes Metastases and Metabolic Reprogramming of Macrophages in the Bone Niche (CUT&RUN)

Project description:Bone metastasis is a major cause of cancer death; however, the epigenetic determinants driving this process remain elusive. Here, we uncover that histone methyltransferase ASH1L is genetically amplified in metastatic diseases and is required for cancer invasiveness and bone metastasis. In invading cancer cells, ASH1L rewires methylations at H3K4 and H3K36 and cooperates with transcriptional factor HIF-1α to induce pro-metastatic transcriptome. Leveraging our newly developed metastasis models and single-cell transcriptomic profiling, we demonstrate that ASH1L in invading cancer cells induces monocyte differentiation into lipid-associated macrophage (LA-TAM) and maintains their pro-tumoral and anti-inflammatory phenotype in the metastatic bone niche. Mechanistic studies reveal that IGF-2 is a direct target of ASH1L and mediates LA-TAMs’ differentiation and phenotypic changes by reprogramming oxidative phosphorylation. In patients with metastatic cancers, ASH1L overexpression is associated with enriched LA-TAMs. As a proof of concept, pharmacologic inhibition of the ASH1L-macrophages axis elicits robust anti-metastasis responses in preclinical models.

2025-03-20 | GSE269829 | GEO

Histone Methyltransferase ASH1L Primes Metastases and Metabolic Reprogramming of Macrophages in the Bone Niche

Project description:ASH1L promotes cancer metastasis, we performed single-cell RNA sequencing (scRNA-seq) to investigate the impact of ASH1L on the crosstalk of invading cancer cells and immune cells in metastatic bone niches

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Rhodes2019 - Immune-Mediated theory of Metastasis

Project description:Abstract: Accumulating experimental and clinical evidence suggest that the immune response to cancer is not exclusively anti-tumor. Indeed, the pro-tumor roles of the immune system - as suppliers of growth and pro-angiogenic factors or defenses against cytotoxic immune attacks, for example - have been long appreciated, but relatively few theoretical works have considered their effects. Inspired by the recently proposed "immune-mediated" theory of metastasis, we develop a mathematical model for tumor-immune interactions at two anatomically distant sites, which includes both anti- and pro-tumor immune effects, and the experimentally observed tumor-induced phenotypic plasticity of immune cells (tumor "education" of the immune cells). Upon confrontation of our model to experimental data, we use it to evaluate the implications of the immune-mediated theory of metastasis. We find that tumor education of immune cells may explain the relatively poor performance of immunotherapies, and that many metastatic phenomena, including metastatic blow-up, dormancy, and metastasis to sites of injury, can be explained by the immune-mediated theory of metastasis. Our results suggest that further work is warranted to fully elucidate the pro-tumor effects of the immune system in metastatic cancer.

2024-09-02 | BIOMD0000000926 | BioModels

ASH1L regulates gene expression in lung cancer

Project description:ASH1L is frequently amplified and mutated in various human cancers, including lung adenocarcinoma, liver, uterine and balder cancers. We used two shRNAs to knockdown endogenous ASH1L proteins in A549 cells, and carried out RNA-seq analysis to identified the genes regulated by ASH1L. We found that compared with the control cells, 541 genes were upregulated in both ASH1L knockdown cells, whereas 398 genes were upregulated. Ingenuity Pathway Analysis (IPA) revealed that the downregulated genes are enriched in fundamental cellular activities, including cell cycle, replication, cell death and survival, and cell growth, and are important for caner and some other diseases . Gene Ontology (GO) analysis also revealed similar cellular pathways that the downregulated genes are involved, whereas the upregulated genes are not enriched in any specific pathways that are statistically significant. Taken together, these data suggest that ASH1L has an oncogenic role in lung adenocarcinoma promoting cancer cell growth, therefore may serve as a potential therapeutic target for the treatment of lung adenocarcinoma patients that have ASH1L amplifications.

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The Disabled homolog 2 controls pro-metastatic activity of tumor-associated macrophages

Project description:Tumor-associated macrophages (TAMs) are regulators of extracellular matrix (ECM) remodeling and metastatic progression, the main cause of cancer-associated death. We found that disabled 2 mitogen-responsive phosphoprotein (DAB2) is highly expressed in tumor-infiltrating TAMs and its genetic ablation significantly impairs lung metastasis formation. DAB2-expressing TAMs, mainly localized along the tumor invasive front, participate in integrin recycling, ECM remodeling and directional migration in a tridimensional matrix. DAB2+ macrophages escort the invasive dissemination of cancer cells by a mechanosensing pathway requiring the transcription factor Yes-Associated Protein. In human lobular breast and gastric carcinomas, DAB2+ TAMs correlated with a poor clinical outcome, identifying DAB2 as potential prognostic biomarker for cancer patient stratification. DAB2 is therefore central for the pro-metastatic activity of TAMs.

2020-07-13 | GSE152674 | GEO

ASH1L links histone H3 lysine 36 di-methylation to leukemia

Project description:The histone methyltransferases MLL and ASH1L are trithorax-group proteins that interact genetically through undefined molecular mechanisms to regulate developmental and hematopoietic gene expression. Here we show that the lysine 36-dimethyl mark of histone H3 (H3K36me2) written by ASH1L is preferentially bound in vivo by LEDGF, an MLL-associated protein that co-localizes with MLL, ASH1L and H3K36me2 on chromatin genome wide. Furthermore, ASH1L facilitates recruitment of LEDGF and wild type MLL proteins to chromatin at key leukemia target genes, and is a crucial regulator of MLL-dependent transcription and leukemic transformation. Conversely KDM2A, an H3K36me2 demethylase and Polycomb-group silencing protein, antagonizes MLL-associated leukemogenesis. Our studies illuminate the molecular mechanisms underlying epigenetic interactions wherein placement, interpretation and removal of H3K36me2 contribute to the regulation of gene expression and MLL leukemia, and suggest ASH1L as a target for therapeutic intervention. Investigation of multiple transcription factors and histone modification marks in MV4-11 human leukemia cells.

2016-07-01 | E-GEOD-73528 | biostudies-arrayexpress

Effect of CSF1R inhibition in tumor macrophages on gene expression in metastatic epithelial cells

Project description:Metastasis is the primary cause of mortality in breast cancer patients. Tumor associated macrophages (TAMs) are active collaborators in mediating several steps of the tumor metastatic cascade, but the molecular details governing this collaboration remain ill-defined. Colony Stimulating Factor 1 (CSF1), a factor critical for macrophage differentiation and survival, functions to recruit TAMs to the primary tumor site, and anti-CSF1 therapies are in clinical trials.In this study, we tested the effect of inhibiting CSF1 signaling in macrophages on gene expression in metastatic tumor cells in mouse models of breast cancer metastasis. Tumor cells were sorted from lung metastases from control and CSF1R inhibitor treated mice. Several pro-tumor processes were significantly affected by CSF1R inhibitor treatment, including angiogenesis and tumor cell proliferation. In addition, a 29 gene signature derived from this data could retrospectively predict survival in a cohort of luminal B breast cancer patients. Collectievly, our results highlight the utility of employing CSF1R inhibitors for the treatment of metastatic breast cancer. GFP tagged MVT1 metastatic mammary tumor cells were injected intravenously into FVB/N mice. Mice were gavaged with the CSF1R inhibitor GW2580 or vehicle starting one week post injection. GFP tagged tumor cells were sorted from metastatic tumor bearing lungs 1 and 2 weeks post injection from 2 vehicle treated mice for each. These are denoted 1_week_WT and 2_week_WT respectively. GFP tagged tumor cells were simultaneously sorted from mice gavaged with GW2580. These samples are denoted 2_week_GW. RNA was extracted and gene expression profiling was performed using the Affymetrix Mouse Genome 430 2.0 Array platform.

2014-03-13 | E-GEOD-55855 | biostudies-arrayexpress

ChIP-seq BHT-101 cells and BHT-101 ASH1L KO cell lines

Project description:The goal of this study is to assess the role of ASH1 like histone lysine methyltransferase (ASH1L) in the biology of anaplastic thyroid cancer. CRISPR-Cas9 was used to create cell lines derived from BHT-101 anaplastic thyroid cancer cells with premature stop codons prior to the catalytic domain within both alleles of ASH1L. ChIP-seq for H3K36me2, the histone mark catalyzed by ASH1L, was performed on two KO cell lines, and compared to wild type BHT-101 cells.

2020-05-09 | GSE147074 | GEO

Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation

Project description:The ASH1L lysine methyltransferase plays a critical role in development and is frequently dysregulated in cancer and neurodevelopmental diseases. ASH1L catalyzes mono- and dimethylation of histone H3K36 and contains a set of uncharacterized domains. Here, we report the structure-function relationships of the C-terminal cassette of ASH1L encompassing a bromodomain (BD), a PHD finger and a bromo-associated homology (BAH) domain and show that ASH1L co-localizes with H3K4me3 but not with H3K36me2 at transcription start sites genome-wide and is involved in embryonic stem cell differentiation and transcriptional regulation of differentiation marker genes. Our crystal and NMR structural data provide mechanistic details for the recognition of H3K4me3 by PHD, the DNA binding activities of BD and BAH, and crosstalk among these domains. We show that the PHD-H3K4me3 interaction is inhibitory to the catalytic activity of ASH1L and that the DNA binding function of BAH is necessary for ASH1L engagement with the nucleosome. Our findings suggest a mechanism by which the C-terminus of ASH1L associates with chromatin and provide molecular and structural insights that are essential in therapeutic targeting of ASH1L.

2023-04-23 | GSE199438 | GEO

Histone H3K36me2-specific methyltransferase ASH1L promotes the MLL-AF9-induced leukemogenesis

Project description:ASH1L and MLL1 are two histone methyltransferases that facilitate transcriptional activation during normal development. However, the roles of ASH1L and its enzymatic activity in the development of MLL-rearranged leukemias are not fully elucidated in Ash1L gene knockout animal models. In this study, we used an Ash1L conditional knockout mouse model to show that loss of ASH1L in hematopoietic progenitor cells impaired the initiation of MLL-AF9-induced leukemic transformation in vitro. Furthermore, genetic deletion of ASH1L in the MLL-AF9-transformed cells impaired the maintenance of leukemic cells in vitro and largely blocked the leukemia progression in vivo. Importantly, the loss of ASH1L function in the Ash1L-deleted cells could be rescued by wild-type but not the catalytic-dead mutant ASH1L, suggesting the enzymatic activity of ASH1L was required for its function in promoting MLL-AF9-induced leukemic transformation. At the molecular level, ASH1L enhanced the MLL-AF9 target gene expression by directly binding to the gene promoters and modifying the local histone H3K36me2 levels. Thus, our study revealed the critical functions of ASH1L in promoting the MLL-AF9-induced leukemogenesis, which provides a molecular basis for targeting ASH1L and its enzymatic activity to treat MLL-arranged leukemias.

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