Integrative analysis of transcriptomics and clinical data uncovers the tumorsuppressive activity of MITF in prostate cancer
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PROVIDER: PRJNA471056 | ENA |
REPOSITORIES: ENA
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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: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.
| S-EPMC6181952 | biostudies-literature
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 MITF-low melanoma transcriptional signature is predictive of poor outcome for patients but little is known about its biological signature. We used genetic models of zebrafish with low expression of mitfa (MITF-low) to study this biological subtype. We performed whole bulk RNA-seq to classify zebrafish MITF-low melanoma that cluster mainly by their directionality of growth and assess their resemblance to patients’ MITF-low subgroups. Furthermore, using genetic inhibition of MITF activity we discover minimal residual disease at the site of regression and using single-cell and low input RNA-seq we characterise these MITF independent cells and show that they pre-exist in the primary tumour.
2019-10-09 | GSE130037 | GEO
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:Role of MITF in advanced lethal prostate cancer
| PRJNA553232 | ENA
Project description:MITF-low zebrafish melanomas reveal cells with no MITF activity at the site of residual disease
| PRJNA533623 | ENA
Project description:MITF, a basic-Helix-Loop-Helix Zipper (bHLHZip) transcription factor, plays vital roles in melanocyte development and functions as an oncogene. We performed a genetic screen for suppressors of the Mitf-associated pigmentation phenotype in mice and identified an intragenic Mitf mutation that terminates MITF at the K316 SUMOylation site, leading to loss of the C-end intrinsically disordered region (IDR). The resulting protein is more nuclear but less stable than wild-type MITF and retains DNA-binding ability. Interestingly, as a dimer, it can translocate wild-type and mutant MITF partners into the nucleus, improving its own stability thus ensuring nuclear MITF supply. To further understand the effect of the suppressor mutation (MITF-sl), we performed CUT&RUN experiments to determine how MITF-sl affects the genome-wide occupancy of MITF. MITF-sl had a higher number of peaks than MITF-WT, with 10,636 peaks (p<0.01) exhibiting statistically significant differences (p < 0.01) between MITF-WT and MITF-sl. Gene ontology analysis indicates that the peaks significantly different between MITF-WT and MITF-sl are associated with genes involved in axonogenesis, axon development, cell growth, and positive regulation of MAPK cascade biological pathways. Our results suggest that the 316-419 domain is critical for selective genome occupancy and transcriptional activation of MITF.
2024-11-06 | GSE267956 | GEO
Project description:We evaluated two matched human cell lines derived from primary melanocytes, termed pmel+BRAF(V600E) and pmel+BRAF(V600E)+MITF. These cells are therefore isogenic with the exception of the expression of MITF. Gene Set Enrichment Analysis of microarray data identified a highly significant induction of oxidative phosphorylation gene set in MITF expressing cells compared to control cells.
2013-03-07 | E-GEOD-38007 | 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.
2023-03-11 | PXD030527 | Pride