Histone demethylase UTX/KDM6A enhances tumor immune cell recruitment, promotes differentiation and suppresses medulloblastoma

Yi, Jiaqing; Shi, Xuanming; Xuan, Zhenyu; Wu, Jiang

doi:10.1016/j.canlet.2020.11.031

Cited by 30 publications

(19 citation statements)

References 73 publications

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“…Other minor cell populations include OLIG2 + cancer stem cells (19), other neuron subtypes, astrocytes, microglia (22), fibroblasts, and blood vessel cells. We and others also observed the recruitment of immune cells to SHH medulloblastomas (23,24). These studies demonstrated the complexity of SHH medulloblastomas and the sensitivity of SHH medulloblastomas to TME changes.…”

Section: Introductionsupporting

confidence: 69%

“…Since CGNP normally is restricted to the granule neuron fate, EED deletion may result in an abnormal fate change to glial cells. We previously showed that a proneural gene NeuroD2 is activated by H3K27me3 demethylase UTX and promotes granule neuron differentiation (24). Antibody staining showed that NEUROD2 was expressed in differentiating granule neurons in the inner EGL and mature neurons in the inner granule layer (IGL) in the control P5 cerebellum but displayed increased expression and abnormal distributions in the Eed-deleted cerebellum (Figure 1E, arrow).…”

Section: Eed Is Required For Normal Mouse Cerebellar Developmentmentioning

confidence: 89%

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A Novel Oncogenic Function of PRC2 Heterogeneity in Medulloblastoma

Shi²,

Zhan³

et al. 2021

Preprint

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Intratumor epigenetic heterogeneity is emerging as a key mechanism underlying tumor evolution and drug resistance. Medulloblastomas, the most common childhood malignant brain tumor, are classified into four subtypes including SHH medulloblastomas, which are characterized by elevated SHH signaling and a cerebellum granule neuron precursor (CGNP) cell-of-origin. Medulloblastomas are highly associated with epigenetic abnormalities. We observed that the histone H3K27 methyltransferase polycomb repressor complex 2 (PRC2) is often heterogeneous within individual SHH medulloblastoma tumors. Using mouse models, we showed that while a complete deletion of the PRC2 core subunit EED inhibited medulloblastoma growth, a mosaic deletion of EED significantly enhanced tumor growth. EED is intrinsically required for CGNP maintenance by inhibiting both neural differentiation and cell death. Complete EED deletion led to CGNP depletion and reduced occurrence of medulloblastoma. Surprisingly, we found that medulloblastomas with mosaic EED levels grew faster than did control wildtype tumors and expressed increased levels of oncogenes such as Igf2. Igf2 is directly repressed by PRC2 and has been demonstrated to be both necessary and sufficient for SHH medulloblastoma progression. We showed that IGF2 mediated the oncogenic effects of PRC2 heterogeneity in tumor growth. Using a human medulloblastoma cell line, we generated clones with different EED levels and confirmed that EEDlow cells could stimulate the growth of EEDhigh cells through derepressed IGF2 signals. Thus, PRC2 heterogeneity controls medulloblastoma growth through both intrinsic growth competence and non-cell autonomous mechanisms in distinct tumor subclones. We reveal a novel oncogenic function of PRC2 heterogeneity in tumor development.

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Section: Introductionsupporting

confidence: 69%

Section: Eed Is Required For Normal Mouse Cerebellar Developmentmentioning

confidence: 89%

A Novel Oncogenic Function of PRC2 Heterogeneity in Medulloblastoma

Shi²,

Zhan³

et al. 2021

Preprint

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“…Recurrent KDM6A mutations have been previously reported in CP-CML [ 7 ]. KDM6A is a histone lysine demethylase and a tumor suppressor, that is recurrently mutated in AML (acute myeloid leukemia) [ 13 ], multiple myeloma (MM) [ 14 ], and solid tumors [ 15 ]. KDM6A is a key regulator of the development and the phenotype of various immune cells, such as NK [ 16 ], NKT [ 17 ], and T cells [ 18 ].…”

mentioning

confidence: 99%

Epigenetic modifier gene mutations in chronic myeloid leukemia (CML) at diagnosis are associated with risk of relapse upon treatment discontinuation

et al. 2022

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“…For instance, a recurrent KDM6A mutation, which is most frequently mutated in G4 MB in the Caucasian cohort ( Northcott et al, 2017 ), but was not detected in G4 MBs in the Asian cohort ( Figure 1D ). The H3K27me3 demethylase KDM6A was reported to have a tumor suppressor function in medulloblastoma ( Yi et al, 2020 ). Conversely, several recurrent mutations in the Asian cohort occurred rarely in the Caucasian cohort, including SHROOM2 , encoding a key mediator of RhoA–ROCK pathway to inhibit tumor metastasis ( Yuan et al, 2019 ), and ADGRV1 , encoding an adhesion G protein-coupled receptor V1 associated with tumor invasion and metastasis ( Aust et al, 2016 ), in SHH-MB, KMT2C , encoding a lysine methyltransferase 2C that regulates MB tumorigenesis ( Roussel and Stripay, 2018 ) in G3-MB, ZFHX3 (zinc finger homeobox 3), ATM , encoding ataxia telangiectasia mutated protein kinase, a DNA damage checkpoint-regulator, and ADGRV1 in G4-MB ( Figure 1D ).…”

Section: Resultsmentioning

confidence: 99%

Genomic and Transcriptomic Analyses Reveals ZNF124 as a Critical Regulator in Highly Aggressive Medulloblastomas

Luo

Dong

et al. 2021

Front. Cell Dev. Biol.

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Medulloblastoma (MB) is the most common malignant pediatric brain tumor, however, the mechanisms underlying tumorigenesis in different MB subgroups remain incompletely understood. Although previous studies of MB predisposition have been conducted in tertiary referral centers primarily in Caucasian cohorts, it is not unclear clear whether there exist population-specific genetic alterations in MBs. In this study, we investigated the contribution of genomic and transcriptomic alterations to the risk of malignant MB in the Chinese population (designated as the Asian cohort). We analyze the genomic and transcriptomic alterations of the Asian MB cohort by using a combination of whole-exome sequencing (WES) and RNA-deep-sequencing. In addition, we integrate publicly available data with the Asian MB cohort and identify a subset of potential MB-driving genes specifically enriched in each of the MB subgroups. We further characterize a newly identified group-3-enriched transcriptional regulator, ZNF124, and demonstrate that ZNF124 is critical for the growth of the most aggressive group-3 MB cells. Together, our analyses indicate conserved yet distinct genetic alterations and gene expression patterns of MBs between different ethnic groups. Our studies further provide an important resource for identifying potential tumor-driving factors in MBs, enhancing our understanding of the disease process for developing ethnically targeted therapies in patients with MB.

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Histone demethylase UTX/KDM6A enhances tumor immune cell recruitment, promotes differentiation and suppresses medulloblastoma

Cited by 30 publications

References 73 publications

A Novel Oncogenic Function of PRC2 Heterogeneity in Medulloblastoma

A Novel Oncogenic Function of PRC2 Heterogeneity in Medulloblastoma

Epigenetic modifier gene mutations in chronic myeloid leukemia (CML) at diagnosis are associated with risk of relapse upon treatment discontinuation

Genomic and Transcriptomic Analyses Reveals ZNF124 as a Critical Regulator in Highly Aggressive Medulloblastomas

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