Upregulation of DLX2 Confers a Poor Prognosis in Glioblastoma Patients by Inducing a Proliferative Phenotype

Yan, Zhengcun; Bao, Zhen; Wang, Yan; Liu, Y.-W.; Zhang, C.-B.; Wang, H.-J.; Feng, Yanjun; Wang, Y.-Z.; Zhang, W.; You, Guoxiang; Zhang, Q.-G.; Tang, Jun‐Ming

doi:10.2174/156652413805076885

Cited by 12 publications

(2 citation statements)

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“…In the TMB‐high category, upregulated mRNAs were found in a subset of the samples. Noteworthy, a number of DLX genes ( DLX1, DLX2, and DLX5 ; Tables and ) previously described in GBM prognosis [31] were upregulated. Median CI was associated with upregulation of 34 transcripts.…”

Section: Individualized Treatmentmentioning

confidence: 99%

Genomic profiling of newly diagnosed glioblastoma patients and its potential for clinical utility – a prospective, translational study

et al. 2020

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Glioblastoma (GBM) is an incurable brain tumor for which new treatment strategies are urgently needed. Next-generation sequencing of GBM has most often been performed retrospectively and on archival tissue from both diagnostic and relapse surgeries with limited knowledge of clinical information, including treatment given. We sought to investigate the genomic composition prospectively in treatment-na€ ıve patients, searched for possible targetable aberrations, and investigated for prognostic and/or predictive factors. A total of 108 newly diagnosed GBM patients were included. Clinical information, progression-free survival, and overall survival (OS) were noted. Tissues were analyzed by whole-exome sequencing, single nucleotide polymorphism (SNP) and transcriptome arrays, and RNA sequencing; assessed for mutations, fusions, tumor mutational burden (TMB), and chromosomal instability (CI); and classified into GBM subgroups. Each genomic report was discussed at a multidisciplinary tumor board meeting to evaluate for matching trials. From 111 consecutive patients, 97.3% accepted inclusion in this study. Eighty-six (77%) were treated with radiation therapy/temozolomide (TMZ) and adjuvant TMZ. One NTRK2 and three FGFR3-TACC3 fusions were identified. Copy number alterations in GRB2 and SMYD4 were significantly correlated with worse median OS together with known clinical variables like age, performance status, steroid dose, and O6-methyl-guanine-DNA-methyl-transferase status. Patients with CI-median or TMB-high had significantly worse median OS compared to CI-low/high or TMB-low/median. In conclusion, performing genomic profiling at diagnosis enables evaluation of genomic-driven therapy at the first progression. Furthermore, TMB-high or CI-median patients had worse median OS, which can support the possibility of offering experimental treatment already at the first line for this group.

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Section: Individualized Treatmentmentioning

confidence: 99%

Genomic profiling of newly diagnosed glioblastoma patients and its potential for clinical utility – a prospective, translational study

et al. 2020

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“…In breast cancer, DLX homeoproteins have been shown to enhance metastatic potential, and DLX4 is capable of regulating epithelial-to-mesenchymal transition by augmenting TWIST levels [ 9 ]. Similarly, in glioblastoma patients, upregulation of DLX2 promotes tumor cell proliferation and is associated with reduced patient survival [ 10 ]. In ovarian cancer, DLX5 promotes cell proliferation via upregulation of AKT signaling through the direct transactivation of insulin receptor substrate 2 ( IRS2 ) [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

The homeoprotein Dlx5 drives murine T-cell lymphomagenesis by directly transactivating Notch and upregulating Akt signaling

Tan

Sementino

et al. 2017

Oncotarget

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Homeobox genes play a critical role in embryonic development, but they have also been implicated in cancer through mechanisms that are largely unknown. While not expressed during normal T-cell development, homeobox transcription factor genes can be reactivated via recurrent chromosomal rearrangements in human T-cell acute leukemia/lymphoma (T-ALL), a malignancy often associated with activated Notch and Akt signaling. To address how epigenetic reprogramming via an activated homeobox gene might contribute to T-lymphomagenesis, we investigated a transgenic mouse model with thymocyte-specific overexpression of the Dlx5 homeobox gene. We demonstrate for the first time that Dlx5 induces T-cell lymphomas with high penetrance. Integrated ChIP-seq and mRNA microarray analyses identified Notch1/3 and Irs2 as direct transcriptional targets of Dlx5, a gene signature unique to lymphomas from Lck-Dlx5 mice as compared to T-cell lymphomas from Lck-MyrAkt2 mice, which were previously reported by our group. Moreover, promoter/enhancer studies confirmed that Dlx5 directly transactivates Notch expression. Notch1/3 expression and Irs2-induced Akt signaling were upregulated throughout early stages of T-cell development, which promoted cell survival during β-selection of T lymphocytes. Dlx5 was required for tumor maintenance via its activation of Notch and Akt, as tumor cells were highly sensitive to Notch and Akt inhibitors. Together, these findings provide unbiased genetic and mechanistic evidence that Dlx5 acts as an oncogene when aberrantly expressed in T cells, and that it is a novel discovery that Notch is a direct target of Dlx5. These experimental findings provide mechanistic insights about how reactivation of the Dlx5 gene can drive T-ALL by aberrant epigenetic reprogramming of the T-cell genome.

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A gain-of-function senescence bypass screen identifies the homeobox transcription factor DLX2 as a regulator of ATM–p53 signaling

Wang

Sack

et al. 2016

Genes Dev.

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Senescence stimuli activate multiple tumor suppressor pathways to initiate cycle arrest and a differentiation program characteristic of senescent cells. We performed a two-stage, gain-of-function screen to select for the genes whose enhanced expression can bypass replicative senescence. We uncovered multiple genes known to be involved in p53 and Rb regulation and ATM regulation, two components of the CST (CTC1-STN1-TEN1) complex involved in preventing telomere erosion, and genes such as REST and FOXO4 that have been implicated in aging. Among the new genes now implicated in senescence, we identified DLX2, a homeobox transcription factor that has been shown to be required for tumor growth and metastasis and is associated with poor cancer prognosis. Growth analysis showed that DLX2 expression led to increased cellular replicative life span. Our data suggest that DLX2 expression reduces the protein components of the TTI1/TTI2/TEL2 complex, a key complex required for the proper folding and stabilization of ATM and other members of the PIKK (phosphatidylinositol 3-kinase-related kinase) family kinase, leading to reduced ATM-p53 signaling and senescence bypass. We also found that the overexpression of DLX2 exhibited a mutually exclusive relationship with p53 alterations in cancer patients. Our functional screen identified novel players that may promote tumorigenesis by regulating the ATM-p53 pathway and senescence.

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Upregulation of DLX2 Confers a Poor Prognosis in Glioblastoma Patients by Inducing a Proliferative Phenotype

Cited by 12 publications

References 0 publications

Genomic profiling of newly diagnosed glioblastoma patients and its potential for clinical utility – a prospective, translational study

Genomic profiling of newly diagnosed glioblastoma patients and its potential for clinical utility – a prospective, translational study

The homeoprotein Dlx5 drives murine T-cell lymphomagenesis by directly transactivating Notch and upregulating Akt signaling

A gain-of-function senescence bypass screen identifies the homeobox transcription factor DLX2 as a regulator of ATM–p53 signaling

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