Mapping of the master transcription factor MITF in prostate cancer
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ABSTRACT:
PROVIDER: PRJNA996973 | ENA |
REPOSITORIES: ENA
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Project description:“Mi” transcription family members such as TFE3 and TFEB, participate in the pathogenesis of a subgroup of renal cell carcinomas, whereas MITF is key in melanocyte development and also contributes to melanoma, behaving as an oncogene when amplified and facilitating tumor invasiveness and therapy resistance when MITF levels are low. In addition, MITF plays a role in the survival and growth of clear cell sarcoma and pancreatic cancer. In prostate cancer MITF through the regulation of the heat-shock protein CRYAB has been suggested to suppress tumor initiation. However, the role of MITF in advanced therapy resistant lethal stages of the disease remains unknown. To gain insight into the gene network regulated by MITF in prostate cancer, we mapped MITF genomewide in a human prostate cancer cell line (22Rv1) by chromatin immunoprecipitation followed by ultra high-throughput sequencing. This analysis revealed the genomewide locations of MITF in prostate cancer, including the promoter of eIF3B which we further functionally validated through ChIP-PCR and luciferase reporter assays. We propose that the master regulator MITF by regulating a distinct gene network may play key roles in suppressing lethal prostate cancer pathogenesis.
2023-12-22 | GSE237870 | GEO
Project description:Great efforts have been made to identify key molecular aberrations that sustain growth and confer resistance to androgen deprivation therapy (ADT) in advanced prostate cancer (PC), and yet PC remains a lethal disease. Recent years have witnessed the discovery of several master regulator transcription factors that enhance lethal PC aggressiveness and provide actionable targets that may improve patient survival. Here we explore the role of the microphthalmia transcription factor (MITF) in lethal prostate cancer. To identify the mechanisms through which MITF mododulates prostate cancer aggressiveness, we knock-down MITF in three prostate cancer cell lines to identify the MITF regulated effector gene network contributing to lethal prostate cancer. Methods: We compared global transcription of three prostate cancer cell lines transduced with a siRNA control and 2 siRNAs targetting MITF by RNAseq. Results: RNA-seq of MITF knockdown prostate cancer cells uncovered a trasncriptional network of MITF regulated genes Conclusions: MITF regulates a discrette gene network that contributes to prostate cancer aggressiveness
2023-12-22 | GSE133977 | GEO
Project description:The dysregulation of gene expression is an enabling hallmark of cancer. Computational analysis of transcriptomics data from human cancer specimens, complemented with exhaustive clinical annotation, provides an opportunity to identify core regulators of the tumorigenic process. Here we exploit well-annotated clinical datasets of prostate cancer for the discovery of transcriptional regulators relevant to prostate cancer. Following this rationale, we identify Microphthalmia-associated transcription factor (MITF) as a prostate tumor suppressor among a subset of transcription factors. Importantly, we further interrogate transcriptomics and clinical data to refine MITF perturbation-based empirical assays and unveil Crystallin Alpha B (CRYAB) as an unprecedented direct target of the transcription factor that is, at least in part, responsible for its tumor-suppressive activity in prostate cancer. This evidence was supported by the enhanced prognostic potential of a signature based on the concomitant alteration of MITF and CRYAB in prostate cancer patients. In sum, our study provides proof-of-concept evidence of the potential of the bioinformatics screen of publicly available cancer patient databases as discovery platforms, and demonstrates that the MITF-CRYAB axis controls prostate cancer biology.
2018-10-16 | GSE114345 | GEO
Project description:Role of MITF in advanced lethal prostate cancer
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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
Project description:Cutaneous melanoma (CM) and uveal melanoma (UM) both originate from the melanocytic lineage but are primarily driven by distinct oncogenic drivers, BRAF/NRAS or GNAQ/GNA11 respectively. The melanocytic master transcriptional regulator, MITF, is essential for both CM development and maintenance, but its role in UM is largely unexplored. Here, we use zebrafish models to dissect the key UM oncogenic signaling events, and establish the role of MITF in UM tumors. Remarkably, mitfa deficiency was profoundly UM promoting, dramatically accelerating the onset and progression of tumors induced by Tg(mitfa:GNAQQ209L);tp53M214K/M214K. To further explore the role of MITF in GNAQ-driven tumorigenesis, we performed phospho-proteomics and total proteomics on 5 zebrafish GNAQ Tg(mitfa:GNAQQ209L);tp53M214K/M214K tumors and 5 zebrafish GNAQ Tg(mitfa:GNAQQ209L);tp53M214K/M214K;mitfa-/- tumors.
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Project description:We performed bulk RNA-seq on cultured melanoma with up- and down- regulation of the master regulator MITF in A2058 human melanoma cells.
2024-07-01 | GSE167496 | GEO
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
Project description:MITF is the master regulator of the melanocyte lineage and a melanoma lineage oncogene. It controls a wide range of target genes fulfilling many distinct functions, but relatively little is known about how its DNA-binding is regulated to select the correct target genes. The datasets presented here were used investigate the effects of MAPK signaling-induced MITF-acetylation on MITF activity in melanoma cells through ChIP-Seq of wild-type and acetyl-mutant MITF.
2021-02-12 | GSE77437 | GEO
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.
2015-04-02 | GSE61966 | GEO