Dataset Information

Identification of Transcription Factor YY1 as a Regulator of a Prostate Cancer-Specific Pathway Using Proteomic Analysis.

ABSTRACT: Prostate-specific antigen, a biomarker used to diagnose prostate cancer, exhibits poor sensitivity. Although previous studies have focused on identifying a new diagnostic biomarker, the molecules or networks identified in these studies are also present in other cancers, making it difficult to detect prostate cancer specifically. A unique characteristic of the prostate gland is the increased mitochondrial energy metabolism when normal prostate cells progress to cancer cells. Thus, we attempted to find a prostate cancer-specific signature present in this unique environment. Proteins that were differentially expressed between a prostate cell line and three prostate cancer cell lines were identified using proteomic analysis. Not surprisingly, the most prevalent proteins detected by network analysis of proteins that were up-regulated at least 1.2-fold in cancer cells, compared to that in normal prostate cells, were those involved in mitochondrial energy metabolism. In addition, we showed that Yin Yang 1 (YY1) was a major transcription factor involved in regulating energy metabolism. To determine whether YY1 regulates genes associated with mitochondrial energy metabolism in prostate cells, cells were subjected to quantitative polymerase chain reaction analysis in the presence or absence of the YY1 inhibitor NP-001. Notably, inhibition of YY1 resulted in reduced expression of genes related to the Krebs cycle and electron transport chain in prostate cancer cell lines. Based on this finding, we suggest that there is a tumor-specific signature that regulates mitochondrial energy metabolism in prostate cancer cells. This work provides a foundation for further work on identifying a means for the specific diagnosis of prostate cancer.

SUBMITTER: Park A

PROVIDER: S-EPMC5560149 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Identification of Transcription Factor YY1 as a Regulator of a Prostate Cancer-Specific Pathway Using Proteomic Analysis.

Park Arum A Lee Jiyeong J Mun Sora S Kim Doo Jin DJ Cha Byung Heun BH Moon Kyong Tae KT Yoo Tag Keun TK Kang Hee-Gyoo HG

Journal of Cancer 20170720 12

Prostate-specific antigen, a biomarker used to diagnose prostate cancer, exhibits poor sensitivity. Although previous studies have focused on identifying a new diagnostic biomarker, the molecules or networks identified in these studies are also present in other cancers, making it difficult to detect prostate cancer specifically. A unique characteristic of the prostate gland is the increased mitochondrial energy metabolism when normal prostate cells progress to cancer cells. Thus, we attempted to ...[more]

PMID: 28819434

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Project description:In prostate cancer (PCa), and many other hormone-dependent cancers, there is clear evidence for distorted transcriptional control as disease driver mechanisms. Defining which transcription factor (TF) and coregulators are altered and combine to become oncogenic drivers remains a challenge, in part because of the multitude of TFs and coregulators and the diverse genomic space on which they function. The current study was undertaken to identify which TFs and coregulators are commonly altered in PCa. We generated unique lists of TFs (n = 2662), coactivators (COA; n = 766); corepressors (COR; n = 599); mixed function coregulators (MIXED; n = 511), and to address the challenge of defining how these genes are altered we tested how expression, copy number alterations and mutation status varied across seven prostate cancer (PCa) cohorts (three of localized and four advanced disease). Testing of significant changes was undertaken by bootstrapping approaches and the most significant changes were identified. For one commonly and significantly altered gene were stably knocked-down expression and undertook cell biology experiments and RNA-Seq to identify differentially altered gene networks and their association with PCa progression risks. COAS, CORS, MIXED and TFs all displayed significant down-regulated expression (q.value < 0.1) and correlated with protein expression (r 0.4-0.55). In localized PCa, stringent expression filtering identified commonly altered TFs and coregulator genes, including well-established (e.g. ERG) and underexplored (e.g. PPARGC1A, encodes PGC1α). Reduced PPARGC1A expression significantly associated with worse disease-free survival in two cohorts of localized PCa. Stable PGC1α knockdown in LNCaP cells increased growth rates and invasiveness and RNA-Seq revealed a profound basal impact on gene expression (~ 2300 genes; FDR < 0.05, logFC > 1.5), but only modestly impacted PPARγ responses. GSEA analyses of the PGC1α transcriptome revealed that it significantly altered the AR-dependent transcriptome, and was enriched for epigenetic modifiers. PGC1α-dependent genes were overlapped with PGC1α-ChIP-Seq genes and significantly associated in TCGA with higher grade tumors and worse disease-free survival. These methods and data demonstrate an approach to identify cancer-driver coregulators in cancer, and that PGC1α expression is clinically significant yet underexplored coregulator in aggressive early stage PCa.

Dataset Information

Identification of Transcription Factor YY1 as a Regulator of a Prostate Cancer-Specific Pathway Using Proteomic Analysis.

Publications

Identification of Transcription Factor YY1 as a Regulator of a Prostate Cancer-Specific Pathway Using Proteomic Analysis.

Similar Datasets

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