PTEN deletion drives aberrations of DNA methylome and transcriptome in different stages of prostate cancer

Abstract

Phosphatase and tensin homolog located on chromosome 10 (PTEN) is a tumor suppressor gene and one of the most frequently mutated/deleted genes in human prostate cancer (PCa). However, how PTEN deletion would impact the epigenome and transcriptome alterations remain unknown. This hypothesis was tested in a prostate‐specific PTEN−/− (KO) mouse prostatic adenocarcinoma model through DNA methyl‐Seq and RNA‐Seq analyses. Examination of cancer genomic datasets revealed that PTEN is expressed at lower levels in PTEN‐deleted tumor samples than in normal solid tissue samples. Methylome and transcriptome profiling identified several inflammatory responses and immune response signaling pathways, including NF‐kB signaling, IL‐6 signaling, LPS/IL‐1‐mediated inhibition of RXR Function, PI3K in B lymphocytes, iCOS‐iCOSL in T helper cells, and the role of NFAT in regulating the immune response, were affected by PTEN deletion. Importantly, a small subset of genes that showed DNA hypermethylation or hypomethylation was correlated with decreased or increased gene expression including CXCL1. quantitative polymerase chain reaction analyses of representative genes validated the RNA‐Seq results. Histopathological examinations showed that the severity of prostatic intraepithelial neoplasia and inflammation development gradually increased as PTEN null mice aged. Collectively, these findings suggest that loss of PTEN drives global changes in DNA CpG methylation and transcriptomic gene expression and highly associated with several inflammatory and immune molecular pathways during PCa development. These biomarkers could be valuable molecular targets for cancer drug discovery and development against PCa.

Silencing miRNA‑1297 suppresses the invasion and migration of prostate cancer cells via targeting modulation of PTEN and blocking of the AKT/ERK pathway

“…Luminal cells of the prostate, which have been confirmed to be the prime origin of PC, generated tumors with stronger aggressivity under the condition of PTEN loss (31,32). Furthermore, PTEN was also reported to induce abnormal methylome and transcriptome of DNA (22).…”

“…Additionally, loss of PTEN expression indicated an unfavorable prognosis in PC (20,21). The anomaly of DNA methylome and transcriptome was caused by PTEN loss at different stages of PC (22). A previous study indicated that miRNA-1297 promoted cell proliferation via targeting PTEN in testicular germ cell tumors (23).…”

DNA methylome, transcriptome, and prostate cancer prevention by phenethyl isothiocyanate in TRAMP mice

“…Previous work from our laboratory has shown that several dietary phytochemicals including curcumin, tocopherols, and PEITC significantly decrease the incidence of prostatic tumorigenesis and inhibit high-grade PIN in TRAMP mice via regulation of a series of cellular pathways including proliferation, apoptosis, cell cycle arrest, Akt signaling, and Nrf2/ARE-mediated antioxidative stress and detoxification. 20,[34][35][36][37][38][39][40] However, how the epigenome would be impacted during TRAMP PCa tumorigenesis and importantly how PEITC would affect the epigenome remain unknown. Here, we focused on exploring the transcriptomic and epigenomic changes in prostate tumorigenesis of TRAMP mice and how the cancer chemopreventive agent PEITC would impact or reverse these epigenomic-transcriptomic alterations.…”

Chromosome 10 abnormality predicts prognosis of neuroblastoma patients with bone marrow metastasis

“…Marked by the centromere, each chromosome is divided into a long arm (q) and short arm (p). High-risk NB children without MYCN gene amplification at stage IV often show an increase in the number of chromosomes 7, 12 and 17, lost of 11q and 3p alleles, and 17q gains [ 19 ]. However, no specific association between chromosome 10 and neuroblastoma has been reported.…”