<i>PTEN</i> loss is associated with prostate cancer recurrence and alterations in tumor DNA methylation profiles

Geybels, Milan S.; Fang, Min; Wright, Jonathan L.; Qu, Xiaoyu; Bibikova, Marina; Klotzle, Brandy; Fan, Jie; Feng, Ziding; Ostrander, Elaine A.; Nelson, Peter S.; Stanford, Janet L.

doi:10.18632/oncotarget.20940

Cited by 35 publications

(34 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…36 With the rapid development of techniques used to investigate the cancer methylome, several studies have identified candidate risk loci or DMRs for PCa. 7 Furthermore, our sequencing data obtained using this model have confirmed and extended previous observations by providing a plausible mechanistic explanation.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Consequently, novel PCa models that more accurately recapitulate human tumours and the surrounding TME are urgently required, in order to continue to develop and improve PCa treatment. PTEN deletion occurs in ~20% of localized PCa, and is implicated in RT failure [ 8 , 9 ], however, an engraftable mouse syngeneic model with Pten deletion, which can be utilised to investigate host response to radiotherapy has long been lacking. In this study we have developed a syngenic model from the Pten −/− /trp53 −/− transgenic mouse tumour [ 10 ]; the DVL3 cell line (derived from tumour formed from the dorsal, ventral and lateral prostate lobes.…”

Section: Introductionmentioning

confidence: 99%

Investigating Radiotherapy Response in a Novel Syngeneic Model of Prostate Cancer

Haughey

Mukherjee

Steele³

et al. 2020

Cancers

View full text Add to dashboard Cite

The prostate cancer (PCa) field lacks clinically relevant, syngeneic mouse models which retain the tumour microenvironment observed in PCa patients. This study establishes a cell line from prostate tumour tissue derived from the Pten−/−/trp53−/− mouse, termed DVL3 which when subcutaneously implanted in immunocompetent C57BL/6 mice, forms tumours with distinct glandular morphology, strong cytokeratin 8 and androgen receptor expression, recapitulating high-risk localised human PCa. Compared to the commonly used TRAMP C1 model, generated with SV40 large T-antigen, DVL3 tumours are immunologically cold, with a lower proportion of CD8+ T-cells, and high proportion of immunosuppressive myeloid derived suppressor cells (MDSCs), thus resembling high-risk PCa. Furthermore, DVL3 tumours are responsive to fractionated RT, a standard treatment for localised and metastatic PCa, compared to the TRAMP C1 model. RNA-sequencing of irradiated DVL3 tumours identified upregulation of type-1 interferon and STING pathways, as well as transcripts associated with MDSCs. Upregulation of STING expression in tumour epithelium and the recruitment of MDSCs following irradiation was confirmed by immunohistochemistry. The DVL3 syngeneic model represents substantial progress in preclinical PCa modelling, displaying pathological, micro-environmental and treatment responses observed in molecular high-risk disease. Our study supports using this model for development and validation of treatments targeting PCa, especially novel immune therapeutic agents.

show abstract

“…PTEN loss or point mutation is frequently observed in advanced PCa. Heterozygous loss of NKX3.1 occurs in PCa and this gene functions as a tumor suppressor . However, precise causal lesions have yet to be identified.…”

Section: Introductionmentioning

confidence: 99%

“…Heterozygous loss of NKX3.1 occurs in PCa and this gene functions as a tumor suppressor. 7,8 However, precise causal lesions have yet to be identified. The paucity of published data is particularly acute in China, where the aging population presents an increasingly heavy medical burden.…”

Section: Introductionmentioning

confidence: 99%

TWIST2: A new candidate tumor suppressor in prostate cancer

et al. 2019

View full text Add to dashboard Cite

Background Prostate cancer (PCa) is a leading cause of cancer morbidity and mortality in men worldwide; however, PCa incidence and mortality rates vary widely across geographic regions and ethnic groups. The current study was designed to elucidate the pivotal factors involved in PCa occurrence and development. Methods We performed RNA sequencing on the prostate tumor and adjacent normal tissues from Chinese PCa patients. Genes identified via genome‐wide expression profile analysis were validated by quantitative reverse‐transcription polymerase chain reaction and immunohistochemistry. Hypermethylation of CpG islands was assessed by nested methylation‐specific PCR. Whole genome microarray analysis was performed using an Affymetrix GeneChip. Results We identified nine possible abnormally expressed genes (P < .05) and then revealed TWIST2 as having strikingly lower expression in tumors than in control tissues (P < .01). Low messenger RNA expression levels of TWIST2 were associated with hypermethylation of CpG islands in its promoter region. In accordance with these findings, PCa tumor tissues showed markedly decreased TWIST2 protein expression compared to that in both normal and prostatic intraepithelial neoplasia tissues by immunohistochemical staining. Ectopic expression of TWIST2 in LNCap cells not only inhibited cell proliferation and colony formation in vitro and tumor growth in vivo but also induced transcriptional repression of a cell proliferation‐related gene cohort, including androgen receptor signaling mediators, cyclins, homeobox genes, forkhead box genes, and SOX2. Conclusions Our results suggest that TWIST2 could function as a tumor suppressor involved in the pathogenesis of PCa by influencing the expression of target genes and that hypermethylation of the TWIST2 promoter in prostate tumors may be an underlying mechanism for TWIST2 transcriptional silencing.

show abstract

PTEN loss is associated with prostate cancer recurrence and alterations in tumor DNA methylation profiles

Cited by 35 publications

References 47 publications

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

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

Investigating Radiotherapy Response in a Novel Syngeneic Model of Prostate Cancer

TWIST2: A new candidate tumor suppressor in prostate cancer

Contact Info

Product

Resources

About