ASXL2 promotes proliferation of breast cancer cells by linking ERα to histone methylation

Park, U H; Kang, Moo Rim; Kim, E J; Kwon, Young‐Soo; Hur, Wonhee; Yoon, Seung Kew; Song, Bing; Park, J H; Hwang, Jin Taek; Jeong, Ji‐Cheon; Um, Soo‐Jong

doi:10.1038/onc.2015.443

Cited by 46 publications

(48 citation statements)

References 52 publications

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“…Recent work has suggested that the plant homeofinger domain (PHD) of ASXL2 may bind to and influence monomethylation at H3K4 (ref. 55), a mark associated with functional enhancers565758. This potential function of the ASXL2 PHD domain may provide a mechanistic explanation for the observation here of alterations of enhancers with loss of ASXL2.…”

Section: Discussionmentioning

confidence: 68%

ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia

et al. 2017

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Additional sex combs-like (ASXL) proteins are mammalian homologues of additional sex combs (Asx), a regulator of trithorax and polycomb function in Drosophila. While there has been great interest in ASXL1 due to its frequent mutation in leukemia, little is known about its paralog ASXL2, which is frequently mutated in acute myeloid leukemia patients bearing the RUNX1-RUNX1T1 (AML1-ETO) fusion. Here we report that ASXL2 is required for normal haematopoiesis with distinct, non-overlapping effects from ASXL1 and acts as a haploinsufficient tumour suppressor. While Asxl2 was required for normal haematopoietic stem cell self-renewal, Asxl2 loss promoted AML1-ETO leukemogenesis. Moreover, ASXL2 target genes strongly overlapped with those of RUNX1 and AML1-ETO and ASXL2 loss was associated with increased chromatin accessibility at putative enhancers of key leukemogenic loci. These data reveal that Asxl2 is a critical regulator of haematopoiesis and mediates transcriptional effects that promote leukemogenesis driven by AML1-ETO.

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Section: Discussionmentioning

confidence: 68%

ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia

et al. 2017

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“…3 and 4), each of which have been recently shown to bind to BAP1 (Sahtoe et al 2016). The ASXM1 and ASXM2 domains of ASXL proteins have been reported to bind to several nuclear hormone receptors (NHRs), including the androgen receptor (Grasso et al 2012), estrogen receptor (Park et al 2015), and PPARγ (Park et al 2011). …”

Section: Discovery Of the Mammalian Asxl Gene Familymentioning

confidence: 99%

“…For example, although phylogenetic analyses suggest that the PHD domain of ASXL proteins may bind histone H3 lysine 4 trimethyl (H3K4me3) (Aravind and Iyer 2012; Katoh 2015), the function of the carboxy-terminal PHD domain of ASXL proteins is in need of definition. One recent report revealed that the PHD domain of ASXL2 binds H3K4me1 and H3K4me2, but validation of this finding with quantitative measurement of binding affinity and other confirmatory assays was not performed nor were the functions of ASXL1 or ASXL3 PHD domains studied (Park et al 2015). Moreover, the possibility that the ASXL PHD domains may bind to nonhistone proteins remains to be tested.…”

Section: Discovery Of the Mammalian Asxl Gene Familymentioning

confidence: 99%

The Role of Additional Sex Combs-Like Proteins in Cancer

Micol

Abdel‐Wahab

2016

Cold Spring Harb Perspect Med

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Additional sex combs-like (ASXL) proteins are mammalian homologs of Addition of sex combs (Asx), a protein that regulates the balance of trithorax and Polycomb function in Drosophila. All three ASXL family members (ASXL1, ASXL2, and ASXL3) are affected by somatic or de novo germline mutations in cancer or rare developmental syndromes, respectively. Although Asx is characterized as a catalytic partner for the deubiquitinase Calypso (or BAP1), there are domains of ASXL proteins that are distinct from Asx and the roles and redundancies of ASXL members are not yet well understood. Moreover, it is not yet fully clarified if commonly encountered ASXL1 mutations result in a loss of protein or stable expression of a truncated protein with dominant-negative or gain-of-function properties. This review summarizes our current knowledge of the biological and functional roles of ASXL members in development, cancer, and transcription.

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“…The present meta-analysis identified 22 potential secreted biomarkers, of which CXCL16 and CXCL8 have been previously reported as biomarkers in patients with Crohn's disease (87) and in several diseases, including urinary bladder cancer, non-Hodgkin's lymphoma and pulmonary infections (88). A literature review indicated that CXCL8 is linked to autophagy in melanoma cell lines (35) and has been reported in metastasis (37). Here, CXCL8 appeared in the top 50 of modulated genes (Fig.…”

Section: Differential Expression Levelsmentioning

confidence: 63%

A meta‑analysis of transcriptome datasets characterizes malignant transformation from melanocytes and nevi to melanoma

et al. 2018

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Melanoma represents one of the most aggressive malignancies and has a high tendency to metastasize. The present study aims to investigate the molecular mechanisms of two pathways to cancer transformation with the purpose of identifying potential biomarkers. Our approach is based on a meta-analysis of gene expression profiling contrasting two scenarios: A model that describes a transformation pathway from melanocyte to melanoma and a second model where transformation occurs through an intermediary nevus. Data consists of three independent, publicly available microarray datasets from the Gene Expression Omnibus (GEO) database comprising samples from melanocytes, nevi and melanoma. The present analysis identified 808 differentially expressed genes (528 upregulated and 360 downregulated) in melanoma compared with nevi, and 2,331 differentially expressed genes (946 upregulated and 1,385 downregulated) in melanoma compared with melanocytes. Further analysis narrowed down this list, since 682 differentially expressed genes were found in both models (417 upregulated and 265 downregulated). Enrichment analysis identified relevant dysregulated pathways. This article also presented a discussion on significant genes including ADAM like decysin 1, neudesin neurotrophic factor, , apolipoprotein L6, motif chemokine ligand ()8, basic, immunoglobulin-like variable motif containing and . These are of particular interest because they encode secreted proteins hence represent potential blood biomarkers for the early detection of malignant transformation in both scenarios. Cytotoxic T-lymphocyte associated protein 4, an important therapeutic target in melanoma treatment, was also upregulated in both comparisons indicating a potential involvement in immune tolerance, not only at advanced stages but also during the early transformation to melanoma. The results of the present study may provide a research direction for studying the mechanisms underlying the development of melanoma, depending on its origin.

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ASXL2 promotes proliferation of breast cancer cells by linking ERα to histone methylation

Cited by 46 publications

References 52 publications

ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia

ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia

The Role of Additional Sex Combs-Like Proteins in Cancer

A meta‑analysis of transcriptome datasets characterizes malignant transformation from melanocytes and nevi to melanoma

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