Mutated Chromatin Regulatory Factors as Tumor Drivers in Cancer

Koschmann, Carl; Nuñez, Fernando M.; Mendez, Flor; Brosnan-Cashman, Jacqueline A.; Meeker, Alan K.; Löwenstein, Pedro R.

doi:10.1158/0008-5472.can-16-2301

Cited by 49 publications

(39 citation statements)

References 64 publications

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“…Epigenetic plasticity is emerging as an important hallmark of cancer (Barneda-Zahonero and Parra, 2012;Feinberg et al, 2016;Flavahan et al, 2017;Koschmann et al, 2017). Up-regulation of HDAC7 expression in rodent and human cells can cooperate for the neoplastic transformation (Di Giorgio et al, 2013;Lei et al, 2017;Paluvai et al, 2018;Rad et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

HDAC7‐mediated control of tumour microenvironment maintains proliferative and stemness competence of human mammary epithelial cells

et al. 2019

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HDAC7 is a pleiotropic transcriptional coregulator that controls different cellular fates. Here, we demonstrate that in human mammary epithelial cells, HDAC7 sustains cell proliferation and favours a population of stem‐like cells, by maintaining a proficient microenvironment. In particular, HDAC7 represses a repertoire of cytokines and other environmental factors, including elements of the insulin‐like growth factor signalling pathway, IGFBP6 and IGFBP7. This HDAC7‐regulated secretome signature predicts negative prognosis for luminal A breast cancers. ChIP‐seq experiments revealed that HDAC7 binds locally to the genome, more frequently distal from the transcription start site. HDAC7 can colocalize with H3K27‐acetylated domains and its deletion further increases H3K27ac at transcriptionally active regions. HDAC7 levels are increased in RAS‐transformed cells, in which this protein was required not only for proliferation and cancer stem‐like cell growth, but also for invasive features. We show that an important direct target of HDAC7 is IL24 , which is sufficient to suppress the growth of cancer stem‐like cells.

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Section: Introductionmentioning

confidence: 99%

HDAC7‐mediated control of tumour microenvironment maintains proliferative and stemness competence of human mammary epithelial cells

et al. 2019

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“…These studies suggest that the response to therapies for gliomas harboring mutant IDH1 is dependent on the genetic context in which this mutation is found (7,33,34). Also, ATRX inactivation can have profound effects on chromatin structure, which in turn will affect the transcriptional profile of the cells in which this genetic lesion is encountered (35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of 2-Hydroxyglutrate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity

Kadiyala

Carney

Gauss

et al. 2020

Preprint

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Brief Summary: Inhibition of 2-Hydroxyglutrate in mutant-IDH1 glioma in the genetic context of ATRX and TP53 inactivation elicits metabolic-reprograming and anti-glioma immunity. Abstract:Mutant isocitrate-dehydrogenase-1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas.Lower grade mIDH1 gliomas are classified into two molecular subgroups: (i) 1p/19q codeletion/TERT-promoter mutations or (ii) inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work, relates to the gliomas' subtype harboring mIDH1, TP53 and ATRX inactivation. IDH1-R132H is a gain-of-function mutation that converts α-ketoglutarate into 2-hydroxyglutarate (D-2HG). The role of D-2HG within the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. Inhibition of 2HG, when used as monotherapy or in combination with radiation and temozolomide (IR/TMZ), led to increased median survival (MS) of mIDH1 glioma bearing mice. Also, 2HG inhibition elicited anti-mIDH1 glioma immunological memory. In response to 2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in wild-type-IDH1 gliomas. Thus, we combined 2HG inhibition/IR/TMZ with anti-PDL1 immune checkpoint-blockade and observed complete tumor regression in 60% of mIDH1 glioma bearing mice. This combination strategy reduced T-cell exhaustion and favored the generation of memory CD8 + T-cells. Our findings demonstrate that metabolic reprogramming elicits anti-mIDH1 glioma immunity, leading to increased MS and immunological memory. Our preclinical data supports the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients. Introduction:Gliomas are highly infiltrative brain tumors accounting for 32% of all primary central nervous system malignancies (1). With advances in molecular biology and sequencing technologies, a distinct profile of genetic alterations for gliomas has emerged (1-3). A gain-offunction mutation in the gene encoding isocitrate dehydrogenase 1 (IDH1) mutation has been reported in ~46% of all adult gliomas (2) and ~80% of low grade gliomas (3, 4). This mutation results in the replacement of arginine (R) for histidine (H) at amino acid residue 132 (R132H) (5, 6). In gliomas, the IDH1-R132H mutation co-occurs with the following genetic alterations: i) oligodendroglioma-1p/19q co-deletion, TERT promoter mutations, or ii) astrocytoma-inactivation of tumor suppressor protein 53 (TP53) gene and loss of function mutations in alpha thalassemia/mental retardation syndrome X-linked gene (ATRX) (2, 4, 7).The IDH1-R132H neomorphic mutation (mIDH1) confers a gain-of-function catalytic activity, prompting the NADPH-dependent reduction of alpha ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (2-HG) (5, 8,9). The accumulation of 2-HG acts antagonistically to α-KG, competitively inhibiting α-KG-dependent dioxygenases, including the ten-eleven translocation (TET) methylcytosine dioxygenases and Jumonji C (JmjC)...

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“…However, in the past years, with the broad application of NGS sequencing technologies for comprehensive cancer profiling it has been shown that many of the pervasive genetic defects in cancer occur in epigenetic (chromatin) regulators [3]. Such mutations in chromatin writers, readers, erasers, remodelers and even the histone proteins themselves, can lead to global alterations in the chromatin of cells, which in turn can steer the cells to altered epigenetic states and expression programs that contribute to tumorigenesis [4][5][6]. This indicates that genetic alterations of chromatin regulators provide the cancer cell with a very efficient means to rewire its transcriptional programs and adapt quickly to microenvironmental or therapeutic pressures [7].…”

Section: Introductionmentioning

confidence: 99%

Genetic aberrations in chromatin factors are pervasive, mutually exclusive, associated with a high mutational burden and improved response to checkpoint immunotherapy in cancer

Markovska¹,

Rosalia

Stajkovska³

et al. 2019

Preprint

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In recent years, it has been shown that many of the pervasive genetic defects in cancer occur in chromatin modifiers. Herein, we analyzed the distribution and mutual relationships of genetic aberrations in relevant chromatin modifiers in tens of thousands of publicly available cancer datasets. We observed that in general, they are mutually exclusive, and their prevalence is higher in some types of cancers compared to others. Moreover, we observed a strong association between aberrations in selected chromatin modifiers and tumor mutational burden, leading to an improved response to checkpoint immunotherapy. All in all, this study uncovered interesting relationships between chromatin factors and features of cancer, which warrant follow up functional and clinical studies.

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Mutated Chromatin Regulatory Factors as Tumor Drivers in Cancer

Cited by 49 publications

References 64 publications

HDAC7‐mediated control of tumour microenvironment maintains proliferative and stemness competence of human mammary epithelial cells

HDAC7‐mediated control of tumour microenvironment maintains proliferative and stemness competence of human mammary epithelial cells

Inhibition of 2-Hydroxyglutrate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity

Genetic aberrations in chromatin factors are pervasive, mutually exclusive, associated with a high mutational burden and improved response to checkpoint immunotherapy in cancer

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