Abstract 4511: Prostate cancer-specific enrichment ofTP53missense mutations elicits differential, context-dependent biochemical and biologic outcomes

Cellular senescence is a natural tumor suppression mechanism defined by a stable proliferation arrest. In the context of cancer treatment, cancer cell therapy-induced senescence (TIS) is emerging as an omnipresent cell fate decision that can be pharmacologically targeted at the molecular level to enhance the beneficial aspects of senescence. In prostate cancer (PCa), TIS has been reported using multiple different model systems, and a more systematic analysis would be useful to identify relevant senescence manipulation molecular targets. Here we show that a spectrum of PCa senescence phenotypes can be induced by clinically relevant therapies. We found that DNA damage inducers like irradiation and poly (ADP-ribose) polymerase1 (PARP) inhibitors triggered a stable PCa-TIS independent of the p53 status. On the other hand, enzalutamide triggered a reversible senescence-like state that lacked evidence of cell death or DNA damage. Using a small senolytic drug panel, we found that senescence inducers dictated senolytic sensitivity. While Bcl-2 family anti-apoptotic inhibitor were lethal for PCa-TIS cells harboring evidence of DNA damage, they were ineffective against enzalutamide-TIS cells. Interestingly, piperlongumine, which was described as a senolytic, acted as a senomorphic to enhance enzalutamide-TIS proliferation arrest without promoting cell death. Overall, our results suggest that TIS phenotypic hallmarks need to be evaluated in a context-dependent manner because they can vary with senescence inducers, even within identical cancer cell populations. Defining this context-dependent spectrum of senescence phenotypes is key to determining subsequent molecular strategies that target senescent cancer cells.

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Context-Dependent Hormone-Refractory Progression Revealed through Characterization of a Novel Murine Prostate Cancer Cell Line

Cancer Research ◽

10.1158/0008-5472.can-05-3441 ◽

2005 ◽

Vol 65 (24) ◽

pp. 11565-11571 ◽

Cited By ~ 85

Author(s):

Philip A. Watson ◽

Katharine Ellwood-Yen ◽

Jennifer C. King ◽

John Wongvipat ◽

Michelle M. LeBeau ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Line ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Cancer Cell Line ◽

Prostate Cancer Cell Line ◽

Context Dependent ◽

Hormone Refractory

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Mutant p53 elicits context-dependent pro-tumorigenic phenotypes

Oncogene ◽

10.1038/s41388-021-01903-5 ◽

2021 ◽

Author(s):

Jennifer J. McCann ◽

Irina A. Vasilevskaya ◽

Christopher McNair ◽

Peter Gallagher ◽

Neermala Poudel Neupane ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Suppressor ◽

Dna Binding ◽

Mutant P53 ◽

Wild Type ◽

P53 Expression ◽

Transcriptional Profiles ◽

Cancer Types ◽

Context Dependent ◽

Wild Type P53

AbstractThe tumor suppressor gene TP53 is the most frequently mutated gene in numerous cancer types, including prostate cancer (PCa). Specifically, missense mutations in TP53 are selectively enriched in PCa, and cluster to particular “hot spots” in the p53 DNA binding domain with mutation at the R273 residue occurring most frequently. While this residue is similarly mutated to R273C-p53 or R273H-p53 in all cancer types examined, in PCa selective enrichment of R273C-p53 is observed. Importantly, examination of clinical datasets indicated that TP53 heterozygosity can either be maintained or loss of heterozygosity (LOH) occurs. Thus, to mimic tumor-associated mutant p53, R273C-p53 and R273H-p53 isogenic PCa models were developed in the presence or absence of wild-type p53. In the absence of wild-type p53, both R273C-p53 and R273H-p53 exhibited similar loss of DNA binding, transcriptional profiles, and loss of canonical tumor suppressor functions associated with wild-type p53. In the presence of wild-type p53 expression, both R273C-p53 and R273H-p53 supported canonical p53 target gene expression yet elicited distinct cistromic and transcriptional profiles when compared to each other. Moreover, heterozygous modeling of R273C-p53 or R273H-p53 expression resulted in distinct phenotypic outcomes in vitro and in vivo. Thus, mutant p53 acts in a context-dependent manner to elicit pro-tumorigenic transcriptional profiles, providing critical insight into mutant p53-mediated prostate cancer progression.

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Evidence for context-dependent functions of KDM5B in prostate development and prostate cancer

Oncotarget ◽

10.18632/oncotarget.27818 ◽

2020 ◽

Vol 11 (46) ◽

pp. 4243-4252

Author(s):

Bigang Liu ◽

Rahul Kumar ◽

Hseuh-Ping Chao ◽

Rashid Mehmood ◽

Yibing Ji ◽

...

Keyword(s):

Prostate Cancer ◽

Prostate Development ◽

Context Dependent

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Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation

10.1101/2021.05.10.443466 ◽

2021 ◽

Author(s):

Sylvan C Baca ◽

Cassandra Singler ◽

Soumya Zacharia ◽

Ji-Heui Seo ◽

Tunc Morova ◽

...

Keyword(s):

Prostate Cancer ◽

Steady State ◽

Binding Sites ◽

Association Studies ◽

Prostate Cancer Risk ◽

Regulatory Elements ◽

Genome Wide Association Studies ◽

Genetic Determinants ◽

Genome Wide ◽

Context Dependent

Methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs), are widely used to functionally annotate trait-associated variants, but they are limited in identifying context-dependent effects on transcription. To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for nominating variants that impact traits through their effects on chromatin state. CWAS associates the genetic determinants of cistromes (e.g., the genome-wide profiles of transcription factor binding sites or histone modifications) with traits using summary statistics from genome-wide association studies (GWAS). We performed CWASs of prostate cancer and androgen-related traits, using a reference panel of 307 prostate cistromes from 165 individuals. CWAS nominated susceptibility regulatory elements or androgen receptor (AR) binding sites at 52 out of 98 known prostate cancer GWAS loci and implicated an additional 17 novel loci. We functionally validated a subset of our results using CRISPRi and in vitro reporter assays. At 28 of the 52 risk loci, CWAS identified regulatory mechanisms that are not observable via eQTLs, implicating genes with complex or context-specific regulation that are overlooked by current approaches that relying on steady-state transcript measurements. CWAS genes include transcription factors that govern prostate development such as NKX3-1, HOXB13, GATA2, and KLF5. Moreover, CWAS boosts discovery power in modestly sized GWAS, identifying novel genetic associations mediated through AR binding for androgen-related phenotypes, including resistance to prostate cancer therapy. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting context-dependent transcriptional regulation.

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Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation

10.21203/rs.3.rs-514642/v1 ◽

2021 ◽

Author(s):

Matthew Freedman ◽

Sylvan Baca ◽

Cassandra Singler ◽

Soumya Zacharia ◽

Ji-Heui Seo ◽

...

Keyword(s):

Prostate Cancer ◽

Steady State ◽

Binding Sites ◽

Association Studies ◽

Prostate Cancer Risk ◽

Regulatory Elements ◽

Genome Wide Association Studies ◽

Genetic Determinants ◽

Genome Wide ◽

Context Dependent

Abstract Methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs), are widely used to functionally annotate trait-associated variants, but they are limited in identifying context-dependent effects on transcription. To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for nominating variants that impact traits through their effects on chromatin state. CWAS associates the genetic determinants of cistromes (e.g., the genome-wide profiles of transcription factor binding sites or histone modifications) with traits using summary statistics from genome-wide association studies (GWAS). We performed CWASs of prostate cancer and androgen-related traits, using a reference panel of 307 prostate cistromes from 165 individuals. CWAS nominated susceptibility regulatory elements or androgen receptor (AR) binding sites at 52 out of 98 known prostate cancer GWAS loci and implicated an additional 17 novel loci. We functionally validated a subset of our results using CRISPRi and in vitro reporter assays. At 28 of the 52 risk loci, CWAS identified regulatory mechanisms that are not observable via eQTLs, implicating genes with complex or context-specific regulation that are overlooked by current approaches that relying on steady-state transcript measurements. CWAS genes include transcription factors that govern prostate development such as NKX3-1, HOXB13, GATA2, and KLF5. Moreover, CWAS boosts discovery power in modestly sized GWAS, identifying novel genetic associations mediated through AR binding for androgen-related phenotypes, including resistance to prostate cancer therapy. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting context-dependent transcriptional regulation.

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