Alterations in chromosome spatial compartmentalization classify prostate cancer progression

Prostate cancer aggressiveness and metastatic potential are influenced by gene expression, genomic aberrations, and cellular morphology. These processes are in turn dependent in part on the 3D structure of chromosomes, packaged inside the nucleus. Using chromosome conformation capture (Hi-C), we conducted a systematic genome architecture comparison on a cohort of cell lines that model prostate cancer progression, ranging from normal epithelium to bone metastasis. Here, we describe how chromatin compartmentalization identity (A- open vs. B-closed) changes with progression: specifically, we find that 48 gene clusters switch from the B to the A compartment, including androgen receptor, WNT5A, and CDK14. These switches could prelude transcription activation and are accompanied by changes in the structure, size, and boundaries of the topologically associating domains (TADs). Further, compartmentalization changes in chromosome 21 are exacerbated with progression and may explain, in part, the genesis of the TMPRSS2-ERG translocation: one of the main drivers of prostate cancer.  These results suggest that discrete, 3D genome structure changes play a deleterious role in prostate cancer progression. 

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Chromosome compartmentalization alterations in prostate cancer cell lines model disease progression

The Journal of Cell Biology ◽

10.1083/jcb.202104108 ◽

2021 ◽

Vol 221 (2) ◽

Author(s):

Rebeca San Martin ◽

Priyojit Das ◽

Renata Dos Reis Marques ◽

Yang Xu ◽

Justin M. Roberts ◽

...

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Cell Lines ◽

Cancer Progression ◽

Genome Structure ◽

3D Structure ◽

Gene Clusters ◽

Chromosome 21 ◽

Prostate Cancer Progression ◽

Cancer Aggressiveness

Prostate cancer aggressiveness and metastatic potential are influenced by gene expression and genomic aberrations, features that can be influenced by the 3D structure of chromosomes inside the nucleus. Using chromosome conformation capture (Hi-C), we conducted a systematic genome architecture comparison on a cohort of cell lines that model prostate cancer progression, from normal epithelium to bone metastasis. We describe spatial compartment identity (A-open versus B-closed) changes with progression in these cell lines and their relation to gene expression changes in both cell lines and patient samples. In particular, 48 gene clusters switch from the B to the A compartment, including androgen receptor, WNT5A, and CDK14. These switches are accompanied by changes in the structure, size, and boundaries of topologically associating domains (TADs). Further, compartment changes in chromosome 21 are exacerbated with progression and may explain, in part, the genesis of the TMPRSS2-ERG translocation. These results suggest that discrete 3D genome structure changes play a deleterious role in prostate cancer progression. 

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The Mechanics of Prostate Cancer Progression: Toward Characterizing Metastatic Potential as a Function of Cell Contractility

Biophysical Journal ◽

10.1016/j.bpj.2020.11.1192 ◽

2021 ◽

Vol 120 (3) ◽

pp. 168a

Author(s):

Clayton W. Molter ◽

Allen J. Ehrlicher

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Metastatic Potential ◽

Prostate Cancer Progression ◽

Cell Contractility

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Linking obesogenic dysregulation to prostate cancer progression

Endocrine Connections ◽

10.1530/ec-15-0080 ◽

2015 ◽

Vol 4 (4) ◽

pp. R68-R80 ◽

Cited By ~ 16

Author(s):

Renea A Taylor ◽

Jennifer Lo ◽

Natasha Ascui ◽

Matthew J Watt

Keyword(s):

Prostate Cancer ◽

Adipose Tissue ◽

Cancer Progression ◽

Prostate Gland ◽

The Body ◽

Endocrine Function ◽

Low Grade ◽

Prostate Cancer Progression ◽

Cancer Aggressiveness ◽

Increased Risk

The global epidemic of obesity is closely linked to the development of serious co-morbidities, including many forms of cancer. Epidemiological evidence consistently shows that obesity is associated with a similar or mildly increased incidence of prostate cancer but, more prominently, an increased risk for aggressive prostate cancer and prostate cancer-specific mortality. Studies in mice demonstrate that obesity induced by high-fat feeding increases prostate cancer progression; however, the mechanisms underpinning this relationship remain incompletely understood. Adipose tissue expansion in obesity leads to local tissue dysfunction and is associated with low-grade inflammation, alterations in endocrine function and changes in lipolysis that result in increased delivery of fatty acids to tissues of the body. The human prostate gland is covered anteriorly by the prominent peri-prostatic adipose tissue and laterally by smaller adipose tissue depots that lie directly adjacent to the prostatic surface. We discuss how the close association between dysfunctional adipose tissue and prostate epithelial cells might result in bi-directional communication to cause increased prostate cancer aggressiveness and progression. However, the literature indicates that several ‘mainstream’ hypotheses regarding obesity-related drivers of prostate cancer progression are not yet supported by a solid evidence base and, in particular, are not supported by experiments using human tissue. Understanding the links between obesity and prostate cancer will have major implications for the health policy for men with prostate cancer and the development of new therapeutic or preventative strategies.

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Genetic Analysis Reveals a Significant Contribution of CES1 to Prostate Cancer Progression in Taiwanese Men

Cancers ◽

10.3390/cancers12051346 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1346

Author(s):

Chien-Chih Ke ◽

Lih-Chyang Chen ◽

Chia-Cheng Yu ◽

Wei-Chung Cheng ◽

Chao-Yuan Huang ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Cancer Progression ◽

Meta Analysis ◽

Cholesterol Homeostasis ◽

Nucleotide Polymorphisms ◽

Prostate Cancer Progression ◽

Multiple Test Correction ◽

Multiple Test ◽

Cancer Aggressiveness

The genes that influence prostate cancer progression remain largely unknown. Since the carboxylesterase gene family plays a crucial role in xenobiotic metabolism and lipid/cholesterol homeostasis, we hypothesize that genetic variants in carboxylesterase genes may influence clinical outcomes for prostate cancer patients. A total of 478 (36 genotyped and 442 imputed) single nucleotide polymorphisms (SNPs) in five genes of the carboxylesterase family were assessed in terms of their associations with biochemical recurrence (BCR)-free survival in 643 Taiwanese patients with prostate cancer who underwent radical prostatectomy. The strongest association signal was shown in CES1 (P = 9.64 × 10−4 for genotyped SNP rs8192935 and P = 8.96 × 10−5 for imputed SNP rs8192950). After multiple test correction and adjustment for clinical covariates, CES1 rs8192935 (P = 9.67 × 10−4) and rs8192950 (P = 9.34 × 10−5) remained significant. These SNPs were correlated with CES1 expression levels, which in turn were associated with prostate cancer aggressiveness. Furthermore, our meta-analysis, including eight studies, indicated that a high CES1 expression predicted better outcomes among prostate cancer patients (hazard ratio 0.82, 95% confidence interval 0.70–0.97, P = 0.02). In conclusion, our findings suggest that CES1 rs8192935 and rs8192950 are associated with BCR and that CES1 plays a tumor suppressive role in prostate cancer.

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