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Direct Targeting of the Oncogene Microphthalmia-Associated Transcription Factor (MITF) by Fragment-Based Discovery [Cut & Tag]

ABSTRACT: Despite the improvement of therapeutic options for melanoma, patients with advanced metastatic disease are still in high need of durable and tolerated treatments. Analysis of clinical data from patients receiving targeted and/or immunotherapy, along with genetic and functional studies in preclinical melanoma models, show that lineage addiction to MITF is retained throughout disease progression, thus providing the rationale to pursue therapeutic inhibition of MITF. However, direct targeting of MITF or other basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factors is unprecedented. Here, we report on the fragment-based discovery of high-affinity ligands for MITF. Fragment screening by NMR led to the discovery of weak binders to the kink pocket of MITF, which were optimized to sub-micromolar affinity by structure-based design enabled by crystallography and biophysics. Furthermore, NMR experiments and molecular dynamics simulations revealed a dynamic conformational exchange of the two helices in the asymmetric homodimer, which is perturbed by ligand binding. This work advances our knowledge on direct targeting of bHLH-LZ domains and sets the basis to further explore pharmacological inhibition of MITF.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283856 | GEO | 2025/11/26

REPOSITORIES: GEO

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Direct Targeting of the Oncogene Microphthalmia-Associated Transcription Factor (MITF) by Fragment-Based Discovery [RNA-seq]

Project description:Despite the improvement of therapeutic options for melanoma, patients with advanced metastatic disease are still in high need of durable and tolerated treatments. Analysis of clinical data from patients receiving targeted and/or immunotherapy, along with genetic and functional studies in preclinical melanoma models, show that lineage addiction to MITF is retained throughout disease progression, thus providing the rationale to pursue therapeutic inhibition of MITF. However, direct targeting of MITF or other basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factors is unprecedented. Here, we report on the fragment-based discovery of high-affinity ligands for MITF. Fragment screening by NMR led to the discovery of weak binders to the kink pocket of MITF, which were optimized to sub-micromolar affinity by structure-based design enabled by crystallography and biophysics. Furthermore, NMR experiments and molecular dynamics simulations revealed a dynamic conformational exchange of the two helices in the asymmetric homodimer, which is perturbed by ligand binding. This work advances our knowledge on direct targeting of bHLH-LZ domains and sets the basis to further explore pharmacological inhibition of MITF.

2025-11-26 | GSE283855 | GEO

Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma

Project description:Malignant melanoma is an aggressive cancer known for its notorious resistance to most current therapies. The basic helix-loop-helix microphthalmia transcription factor (MITF) is the master regulator determining the identity and properties of the melanocyte lineage, and is regarded as a lineage-specific ‘oncogene’ that has a critical role in the pathogenesis of melanoma. MITF promotes melanoma cell proliferation, whereas sustained supression of MITF expression leads to senescence. By combining chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) and RNA sequen- cing analyses, we show that MITF directly regulates a set of genes required for DNA replication, repair and mitosis. Our results reveal how loss of MITF regulates mitotic fidelity, and through defective replication and repair induces DNA damage, ultimately ending in cellular senescence. These findings reveal a lineage-specific control of DNA replication and mitosis by MITF, providing new avenues for therapeutic intervention in melanoma. The identification of MITF-binding sites and gene- regulatory networks establish a framework for under- standing oncogenic basic helix-loop-helix factors such as N-myc or TFE3 in other cancers. 4 samples corresponding to genomic occupancy profiling of MITF (Cl8), PolII (501Mel), H3K4me3 501Mel). Anti-HA ChIP-seq on untagged cell line (501Mel) was used as a control.

2014-12-13 | E-GEOD-64137 | biostudies-arrayexpress

Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma

2014-12-13 | GSE64137 | GEO

Local Genomic Features Predict the Distinct and Overlapping Binding Patterns of the bHLH‐Zip Family Oncoproteins MITF and MYC‐MAX

Project description:MITF and MYC are well‐known oncoproteins and members of the basic helix‐loop‐helix leucine zipper (bHLH‐Zip) family of transcription factors (TFs) recognizing hexamer E‐box motifs. MITF and MYC not only share the core binding motif, but are also the two most highly expressed bHLH‐Zip transcription factors in melanocytes, raising the possibility that they may compete for the same binding sites in select oncogenic targets. Mechanisms determining the distinct and potentially overlapping binding modes of these critical oncoproteins remain uncharacterized. We introduce computational predictive models using local sequence features, including a boosted convolutional decision tree framework, to distinguish MITF vs. MYC‐MAX binding sites with up to 80% accuracy genome wide. Select E‐box locations that can be bound by both MITF and MYC‐MAX form a separate class of MITF binding sites characterized by differential sequence content in the flanking region, diminished interaction with SOX10, higher evolutionary conservation, and less tissue‐specific chromatin organization.

2018-12-14 | GSE115845 | GEO

KINK-1, a novel small-molecule inhibitor of IKKbeta, enhances susceptibility of melanoma cells to antitumoral treatment

Project description:Interference with chemoresistance to enhance the efficacy of chemotherapeutics may be of great utility for cancer therapy. We have identified KINK-1 (Kinase Inhibitor of NF-kappaB-1), a highly selective small-molecule IKKkappa inhibitor, as a potent suppressor of both constitutive and induced NF-kappaB activity in melanoma cells. While KINK-1 profoundly diminished various NF-kappaB-dependent gene products regulating proliferation, cytokine production or anti-apoptotic responses, the compound by itself showed little antiproliferative or pro-apoptotic activity on the cellular level. However, its combination with some cytostatics markedly enhanced their antitumoral activities in vitro, and doxorubicin-induced NF-kappaB activation, a mechanism implicated in chemoresistance, was abrogated by KINK-1. In addition, when KINK-1 was combined with doxorubicin in an in vivo melanoma model, experimental metastasis was significantly diminished as compared to either treatment alone. Induction of chemoresistance by KINK-1 in vivo was not observed. Thus, KINK-1 or related substances might increase the susceptibility of tumors to chemotherapy. Keywords: time-course

2008-08-09 | GSE8772 | GEO

Transcription profiling of human melanoma cells reveals KINK-1 a novel small-molecule inhibitor of IKK, enhances susceptibility of melanoma cells to antitumoral treatment

Project description:Interference with chemoresistance to enhance the efficacy of chemotherapeutics may be of great utility for cancer therapy. We have identified KINK-1 (Kinase Inhibitor of NF-ï«B-1), a highly selective small-molecule IKKï¢ inhibitor, as a potent suppressor of both constitutive and induced NF-ï«B activity in melanoma cells. While KINK-1 profoundly diminished various NF-ï«B-dependent gene products regulating proliferation, cytokine production or anti-apoptotic responses, the compound by itself showed little antiproliferative or pro-apoptotic activity on the cellular level. However, its combination with some cytostatics markedly enhanced their antitumoral activities in vitro, and doxorubicin-induced NF-ï«B activation, a mechanism implicated in chemoresistance, was abrogated by KINK-1. In addition, when KINK-1 was combined with doxorubicin in an in vivo melanoma model, experimental metastasis was significantly diminished as compared to either treatment alone. Induction of chemoresistance by KINK-1 in vivo was not observed. Thus, KINK-1 or related substances might increase the susceptibility of tumors to chemotherapy. Experiment Overall Design: one control and two time point (12hrs and 24hrs) are analyzed, with one replicate each (6 arrays total)

2008-10-18 | E-GEOD-8772 | biostudies-arrayexpress

BRG1 recruitment by transcription factors MITF and SOX10 defines a specific configuration of regulatory elements in the melanocyte lineage (ChIP-seq)

Project description:Microphthalmia-associated transcription factor (MITF) is the master regulator of the melanocyte lineage. By tandem affinity purification and mass spectrometry, we present a comprehensive characterisation of the MITF interactome comprising multiple novel cofactors involved in transcription, DNA replication and repair and chromatin organisation, including a BRG1 chromatin remodelling complex comprising CHD7. BRG1 is essential for melanoma cell proliferation in vitro and for normal melanocyte development in vivo. MITF and SOX10 actively recruit BRG1 to a set of MITF-associated regulatory elements (MAREs) at active enhancers. MITF, SOX10 and YY1 bind between two BRG1-occupied nucleosomes thus defining both a combinatorial signature of transcription factors essential for the melanocyte lineage and a specific chromatin organisation of MAREs. Nevertheless, BRG1 silencing enhances MITF occupancy at MAREs showing that BRG1 acts to promote dynamic MITF interactions with chromatin. 8 samples corresponding to genomic occupancy profiling of MITF, SOX10, BRG1 after si-control, BRG1 after si-MITF and BRG1 after siSOX10; and their respective controls (MITF Input, SOX10 Input, GFP-siCTRL ChIPseq) in 501Mel cells.

2015-04-02 | E-GEOD-61965 | biostudies-arrayexpress

Altered expression of genes in AP4 knockdown and overexpression

Project description:The transcription factor AP4/TFAP4/AP-4 is a ubiquitously expressed basic helix-loop-helix leucine-zipper (bHLH-LZ) transcription factor, which forms homodimer that binds to the consensus E-box motif 5-CAGCTG-3. Prostatic adenocarcinoma (PAC), also known as prostate cancer, is the second most common malignancy of men with 914,000 new cases and approximately 258,000 deaths worldwide in 2008. The goal of this study is to identify the target genes of AP4 in prostate cancer. Our results demonstrated that the genes regulated by AP4 are involved in a variety of biological functions, such as proliferation and invasion. We used microarrays to detail the different expression of genes in AP4 knockdown and overexpression and identified distinct classes of up-regulated genes during this process.

2016-06-09 | GSE83140 | GEO

Gene expression in germinal centre light zone and dark zone cells

Project description:Gene expression analysis performed on FACS sort purified GC LZ and DZ cells of either high and low affinity to identify unique gene signatures. In order to reveal differences between LZ and DZ independent of affinity, we compared a DZ data set (consisting of high and low affinity samples), to a LZ data set (consisting of high and low affinity samples). Analysis revealed distrinct transcription patterns.

2017-03-27 | GSE94733 | GEO

BRG1 recruitment by transcription factors MITF and SOX10 defines a specific configuration of regulatory elements in the melanocyte lineage (RNA-seq)

Project description:Microphthalmia-associated transcription factor (MITF) is the master regulator of the melanocyte lineage. By tandem affinity purification and mass spectrometry, we present a comprehensive characterisation of the MITF interactome comprising multiple novel cofactors involved in transcription, DNA replication and repair and chromatin organisation, including a BRG1 chromatin remodelling complex comprising CHD7. BRG1 is essential for melanoma cell proliferation in vitro and for normal melanocyte development in vivo. MITF and SOX10 actively recruit BRG1 to a set of MITF-associated regulatory elements (MAREs) at active enhancers. MITF, SOX10 and YY1 bind between two BRG1-occupied nucleosomes thus defining both a combinatorial signature of transcription factors essential for the melanocyte lineage and a specific chromatin organisation of MAREs. Nevertheless, BRG1 silencing enhances MITF occupancy at MAREs showing that BRG1 acts to promote dynamic MITF interactions with chromatin. 19 samples corresponding to mRNA profiles of 501Mel and Hermes3A after MITF, BRG1 or control shRNA-mediated knockdown were generated by deep sequencing in triplicate (in duplicate for 501_shMITF and corresponding control 501_shSCR2), using HiSeq2500.

2015-04-02 | E-GEOD-61966 | biostudies-arrayexpress

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