Abstract
Genome-wide association studies (GWAS) have identified >100 independent susceptibility loci for prostate cancer, including the hot spot at 8q24. However, how genetic variants at this locus confer disease risk hasn’t been fully characterized. Using circularized chromosome conformation capture (4C) coupled with next-generation sequencing and an enhancer at 8q24 as “bait”, we identified genome-wide partners interacting with this enhancer in cell lines LNCaP and C4-2B. These 4C-identified regions are distributed in open nuclear compartments, featuring active histone marks (H3K4me1, H3K4me2 and H3K27Ac). Transcription factors NKX3-1, FOXA1 and AR (androgen receptor) tend to occupy these 4C regions. We identified genes located at the interacting regions, and found them linked to positive regulation of mesenchymal cell proliferation in LNCaP and C4-2B, and several pathways (TGF beta signaling pathway in LNCaP and p53 pathway in C4-2B). Common genes (e.g. MYC and POU5F1B) were identified in both prostate cancer cell lines. However, each cell line also had exclusive genes (e.g. ELAC2 and PTEN in LNCaP and BRCA2 and ZFHX3 in C4-2B). In addition, BCL-2 identified in C4-2B might contribute to the progression of androgen-refractory prostate cancer. Overall, our work reveals key genes and pathways involved in prostate cancer onset and progression.
Highlights
Genome-wide association studies (GWAS) have identified >100 independent susceptibility loci for prostate cancer, including the hot spot at 8q24
We selected two representative prostate cancer cell lines: lymph node cancer of the prostate (LNCaP) cells, which were isolated from lymph node metastasis and are androgen sensitive[24], and C4-2B cells, which were derived from bone metastasis of the LNCaP parental line[25] and can grow in an androgen independent way, but are still responsive to androgen in certain aspects[26]
Using LNCaP and C4-2B cell lines for our 4C-seq analysis, we were able to compare these representative models of androgen sensitive and insensitive prostate cancer
Summary
Genome-wide association studies (GWAS) have identified >100 independent susceptibility loci for prostate cancer, including the hot spot at 8q24. Using circularized chromosome conformation capture (4C) coupled with next-generation sequencing and an enhancer at 8q24 as “bait”, we identified genomewide partners interacting with this enhancer in cell lines LNCaP and C4-2B. These 4C-identified regions are distributed in open nuclear compartments, featuring active histone marks (H3K4me[1], H3K4me[2] and H3K27Ac). We reasoned that the contact landscapes around the 8q24 risk locus revealed by 4C-seq in these two cell lines may shed light on the network(s) regulating prostate cancer initiation and/or progression
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