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Genome-wide analysis of HOXC4 and HOXC6 regulated genes and binding sites in prostate cancer cells

ABSTRACT: Aberrant expression of HOXC6 and HOXC4 is commonly detected in prostate cancer. The high expression of these transcription factors is associated with aggressive prostate cancer and can predict cancer recurrence after treatment. Thus, HOXC4 and HOXC6 are clinically relevant biomarkers of aggressive prostate cancer. However, the molecular mechanisms by which these HOXC genes contribute to prostate cancer is not yet understood. To begin to address the role of HOXC4 and HOXC6 in prostate cancer, we performed RNA-seq analyses before and after siRNA-mediated knockdown of HOXC4 and/or HOXC6 and also performed ChIP-seq to identify genomic binding sites for both of these transcription factors. Our studies demonstrate that HOXC4 and HOXC6 co-localize with HOXB13, FOXA1 and AR, three transcription factors previously shown to contribute to the development of prostate cancer. We suggest that the aberrantly upregulated HOXC4 and HOXC6 proteins may compete with HOXB13 for binding sites, thus altering the prostate transcriptome. This competition model may be applicable to many different human cancers that display increased expression of a HOX transcription factor.

ORGANISM(S): Homo sapiens

PROVIDER: GSE129951 | GEO | 2020/01/22

REPOSITORIES: GEO

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Project description:Although technological advances now allow increased tumor profiling, a detailed understanding of the mechanisms leading to the development of different cancers remains elusive. Our approach towards understanding the molecular events that lead to cancer is to characterize changes in transcriptional regulatory networks between normal and tumor tissue. Because enhancer activity is thought to be critical in regulating cell fate decisions, we have focused our studies on distal regulatory elements and transcription factors that bind to these elements. Using DNA methylation data, we identified more than 25,000 enhancers that are differentially activated in breast, prostate, and kidney tumor tissues, as compared to normal tissues. We then developed an analytical approach called TENET (Tracing Enhancer Networks using Epigenetic Traits) that correlates DNA methylation levels at enhancers with gene expression to identify more than 800,000 genome-wide links from enhancers to genes and from genes to enhancers. We found more than 1,200 transcription factors to be involved in these tumor-specific enhancer networks. We further characterized several transcription factors linked to a large number of enhancers in each tumor type, including GATA3 in non-basal breast tumors, HOXC6 and DLX1 in prostate tumors, and ZNF395 in kidney tumors. We showed that HOXC6 and DLX1 are associated with different clusters of prostate tumor-specific enhancers and confer distinct transcriptomic changes upon knockdown in C42B prostate cancer cells. We also discovered de novo motifs enriched in enhancers linked to ZNF395 in kidney tumors. Our studies characterized tumor-specific enhancers and revealed key transcription factors involved in enhancer networks for specific tumor types and subgroups. Our findings, which include a large set of identified enhancers and transcription factors linked to those enhancers in breast, prostate, and kidney cancers, will facilitate understanding of enhancer networks and mechanisms leading to the development of these cancers. Examination of FAIRE and ChIP assays in prostate and breast epithelial cells. RNA-seq assays in C42B, prostate cancer cell line after knocking down of TFs (HOXC6, DLX1).

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Genome-wide analysis of HOXC4 and HOXC6 regulated genes and binding sites in prostate cancer cells

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