Role of MITF in advanced lethal prostate cancer
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ABSTRACT:
PROVIDER: PRJNA553232 | ENA |
REPOSITORIES: ENA
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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:“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:Prostate cancer is characterized as being histologically and molecularly heterogeneous. Additionally, epigenetic changes play an important role in regulating the progression of prostate cancer. However, epigenetic intraindividual heterogeneity is largely unknown in advanced prostate cancer. Hence, the epigenetic profiles of advanced prostate cancer, including autopsy cases, were investigated.
2024-07-20 | GSE256194 | GEO
Project description:Obese men are at higher risk of developing advanced prostate cancer and have higher rates of cancer-specific mortality. However, the biological mechanisms explaining these associations are unknown. Using gene expression data, we aimed to identify molecular alterations in prostate cancer tissue associated with obesity. Gene Set Enrichment Analysis identified fifteen gene sets up-regulated in the tumor tissue of obese prostate cancer patients (N=84) compared to healthy weight patients (N=192), five of which were related to chromatin remodeling. These gene sets were not identified in an analysis of adjacent normal tissue. Patients with tumors with high expression of chromatin remodeling genes had worse clinical characteristics (Gleason grade >7, 41% versus 17%, p-trend = 3.21 x 10-4) and poorer prostate cancer-specific survival independent of Gleason grade (lethal outcome, OR = 5.01, 95% CI = 2.31 to 11.38). Mediation analysis further supported a role for chromatin remodeling in the obesity-lethal prostate cancer relationship.
2017-03-01 | GSE79021 | 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:MITF, a gene that is mutated in familial melanoma and Waardenburg syndrome, encodes multiple isoforms expressed from alternative promoters that share common coding exons but have unique amino termini. It is not completely understood how these isoforms influence pigmentation in different tissues and how expression of these independent isoforms of MITF are regulated. Here, we show that melanocytes express two isoforms of MITF, MITF-A and MITF-M. Expression of MITF-A is partially regulated by a newly identified retinoid enhancer element located upstream of the MITF-A promoter. Mitf-A knockout mice have only subtle changes in melanin accumulation in the hair and reduced Tyr expression in the eye. In contrast, Mitf-M null mice have enlarged kidneys, lack neural crest derived melanocytes in the skin, choroid, and iris stroma; yet maintain pigmentation within the retinal pigment epithelium and iris pigment epithelium of the eye. Taken together, these studies identify a critical role for MITF-M in melanocytes, a minor role for MITF-A in regulating pigmentation in the hair and Tyr expression in the eye, and a novel role for MITF-M in size control of the kidney.
2019-12-31 | GSE138538 | GEO
Project description:The prostate stromal transcriptome and aggressive and lethal prostate cancer
| PRJNA887775 | ENA
Project description:Epigenetic landscape of advanced prostate cancer
| PRJNA1078399 | ENA
Project description:This SuperSeries is composed of the following subset Series: GSE32967: Modeling lethal prostate cancer variant with small cell carcinoma features [expression profile] GSE33053: Modeling lethal prostate cancer variant with small cell carcinoma features [genomic profile] Refer to individual Series
2012-01-01 | E-GEOD-33054 | biostudies-arrayexpress
Project description:Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains/losses, including ETS gene fusions, PTEN loss and androgen receptor (AR) amplification, that drive prostate cancer development and progression to lethal, metastatic castrate resistant prostate cancer (CRPC)1. As less is known about the role of mutations2-4, here we sequenced the exomes of 50 lethal, heavily-pretreated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment naïve, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPC (2.00/Mb) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1, which define a subtype of ETS? prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in ~1/3 of CRPCs (commonly through TMPRSS2:ERG fusions), is a prostate cancer tumor suppressor that can also be deregulated through mutation. Further, we identified recurrent mutations in multiple chromatin/histone modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with AR, which is required for AR mediated signaling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC) , and showed that mutated FOXA1 represses androgen signaling and increases tumor growth in vitro and in vivo. Proteins that physically interact with AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX, and ASXL1 were found to be mutated in CRPC, suggesting novel drivers of prostate cancer progression and potential resistance mechanisms to anti-androgen therapies. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signaling deregulated in prostate cancer, and prioritize candidates for future study. Gene expression profiling and array CGH (aCGH) was performed on matched benign prostate tissues (n=28), localized prostate cancer (n=59), and metastatic castrate resistant prostate cancer (CRPC, n=35). For gene expression profiling, frozen prostate tissue samples (channel 2), were hybridized against a commercial pool of benign prostate tissue (Clontech, channel 1). For aCGH, frozen prostate tissue samples (channel 2) were hybridized against a commerical sample of Human Male Genomic DNA (Promega, channel 1).
2012-05-22 | E-GEOD-35988 | biostudies-arrayexpress