Prostate cancer reactivates developmental epigenomic programs during metastatic progression

Pomerantz, Mark; Qiu, Xintao; Zhu, Yanyun; Takeda, David Y.; Pan, Wenting; Baca, Sylvan C.; Gusev, Alexander; Korthauer, Keegan; Severson, Tesa; Ha, Gavin; Viswanathan, Srinivas R.; Seo, Ji Heui; Nguyen, Holly M.; Zhang, Baohui; Paşaniuc, Bogdan; Giambartolomei, Claudia; Alaiwi, Sarah Abou; Bell, Connor; O’Connor, Edward; Chabot, Matthew S.; Stillman, David R.; Lis, Rosina T.; Font-Tello, Alba; Li, Lewyn; Cejas, Paloma; Bergman, Andries M.; Sanders, Joyce; Poel, Henk G. van der; Gayther, Simon A.; Lawrenson, Kate; Fonseca, Marcos A. S.; Reddy, Josina C.; Corona, Rosario I.; Martovetsky, Gleb; Egan, Brian; Choueiri, Toni K.; Ellis, Leigh; Garraway, Isla P.; Lee, Gwo Shu Mary; Corey, Eva; Long, Henry W.; Zwart, Wilbert; Freedman, Matthew L.

doi:10.1038/s41588-020-0664-8

Cited by 182 publications

(238 citation statements)

References 93 publications

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“…In prostate tumours, FOXA1 is capable of reprogramming AR binding sites and drives oncogenic programs along with transcription factor HOXB13 ( Fig. 1B) (Pomerantz et al 2015(Pomerantz et al , 2020 . In addition, FOXA1 is reported as a suppressor of neuroendocrine differentiation and its loss of expression can promote NEPC progression (Kim et al 2017;Rotinen et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Pioneer of prostate cancer: past, present and the future of FOXA1

et al. 2020

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Prostate cancer is the most commonly diagnosed non-cutaneous cancers in North American men. While androgen deprivation has remained as the cornerstone of prostate cancer treatment, resistance ensues leading to lethal disease. Forkhead box A1 (FOXA1) encodes a pioneer factor that induces open chromatin conformation to allow the binding of other transcription factors. Through direct interactions with the Androgen Receptor (AR), FOXA1 helps to shape AR signaling that drives the growth and survival of normal prostate and prostate cancer cells. FOXA1 also possesses an AR-independent role of regulating epithelial-to-mesenchymal transition (EMT). In prostate cancer, mutations converge onto the coding sequence and cis-regulatory elements (CREs) of FOXA1, leading to functional alterations. In addition, FOXA1 activity in prostate cancer can be modulated post-translationally through various mechanisms such as LSD1-mediated protein demethylation. In this review, we describe the latest discoveries related to the function and regulation of FOXA1 in prostate cancer, pointing to their relevance to guide future clinical interventions.

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Section: Introductionmentioning

confidence: 99%

Pioneer of prostate cancer: past, present and the future of FOXA1

et al. 2020

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“…In this regard, it would be important to evaluate whether, as reported here for PGCLC induction, the partial decommissioning of enhancers can be involved in their subsequent reactivation and, thus, in the induction of gene expression programs in other developmental contexts. Similar mechanisms might be also important in other physiological 27 and pathological 76, 77 contexts in which a previously used but already dismantled gene expression program gets re-activated.…”

Section: Discussionmentioning

confidence: 94%

Enhancer-associated H3K4 methylation safeguards in vitro germline competence

Bleckwehl

Crispatzu

Schaaf

et al. 2020

Preprint

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SUMMARYGermline specification in mammals occurs through an inductive process whereby competent cells in the post-implantation epiblast reactivate a naïve pluripotency expression program and differentiate into primordial germ cells (PGC). The intrinsic factors that endow epiblast cells with the competence to respond to germline inductive signals remain largely unknown.Here we show that early germline genes that are active in the naïve pluripotent state become homogeneously dismantled in germline competent epiblast cells. In contrast, the enhancers controlling the expression of major PGC genes transiently and heterogeneously acquire a primed state characterized by intermediate DNA methylation, chromatin accessibility, and H3K4me1. This primed enhancer state is lost, together with germline competence, as epiblast cells develop further. Importantly, we demonstrate that priming by H3K4me1/2 enables the robust activation of PGC enhancers and is required for germline competence and specification. Our work suggests that H3K4me1/2 is directly involved in enhancer priming and the acquisition of competence.

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“…A recent epigenetic study further demonstrated an association between prostate lineage-specific regulatory elements and PC risk loci and somatic mutation density in different stages of PC (Pomerantz et al, 2020). Binding of AR prominently occurs at distal regulatory elements (Massie et al, 2011;Yu et al, 2010), and AR-driven regulatory programs are context-dependent (Sharma et al, 2013;Wang et al, 2009) (Pomerantz et al, 2020) (Sharma et al, 2013;Wang et al, 2009). In PC cells, AR (Urbanucci et al, 2012;Yu et al, 2010), FOXA1 (Adams et al, 2019;Parolia et al, 2019;Sahu et al, 2011), HOXB13 (Chen et al, 2018;Pomerantz et al, 2015), ERG, and CHD1 (Augello et al, 2019) have emerged as epigenetic drivers of disease (Stelloo et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…In addition to implicating cancer genes, genome sequencing studies have revealed structural variation in non-coding regions, including enhancer elements driving oncogene expression (Takeda et al, 2018;Viswanathan et al, 2018). Epigenetic characterization studies have further extended understanding of the noncoding genome by revealing the role of DNA methylation patterns (Bedford and van Helden, 1987;Börno et al, 2012;Friedlander et al, 2012;Jimenez et al, 2000;Lee et al, 1997;Mahapatra et al, 2012;Varambally et al, 2002;Xu et al, 2012;Zhao et al, 2020), specific transcription factor (TF) binding sites and histone modifications, including the characterization of the active enhancer landscape in PC tissues (Kron et al, 2017;Pomerantz et al, 2015Pomerantz et al, , 2020Stelloo et al, 2018;Urbanucci et al, 2012Urbanucci et al, , 2017Yu et al, 2010). Still, how the chromatin landscape evolves during PC progression and drives aberrant transcriptome (Cancer Genome Atlas Research Network, 2015) and proteome (Latonen et al, 2018;Sinha et al, 2019), is unclear.…”

Section: Introductionmentioning

confidence: 99%

“…In PC, the study by Corces et al uncovered chromatin accessibility changes at single-nucleotide polymorphism that are associated with increased PC susceptibility and illustrated androgen receptor (AR) binding site enrichment in regulatory regions specific to primary PC (Corces et al, 2018). A recent epigenetic study further demonstrated an association between prostate lineage-specific regulatory elements and PC risk loci and somatic mutation density in different stages of PC (Pomerantz et al, 2020). Binding of AR prominently occurs at distal regulatory elements (Massie et al, 2011;Yu et al, 2010), and AR-driven regulatory programs are context-dependent (Sharma et al, 2013;Wang et al, 2009) (Pomerantz et al, 2020) (Sharma et al, 2013;Wang et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Chromatin accessibility analysis uncovers regulatory element landscape in prostate cancer progression

Uusi-Mäkelä

Afyounian

Tabaro

et al. 2020

Preprint

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Aberrant oncogene functions and structural variation alter the chromatin structure in cancer cells. While gene regulation by chromatin states has been studied extensively, chromatin accessibility and its relevance in aberrant gene expression during prostate cancer progression is not well understood. Here, we report a genome-wide chromatin accessibility analysis of clinical tissue samples of benign prostatic hyperplasia (BPH), untreated primary prostate cancer (PC) and castration-resistant prostate cancer (CRPC) and integrative analysis with transcriptome, methylome, and proteome profiles of the same samples to uncover disease-relevant regulatory elements and their association to altered gene expression during prostate cancer progression. While promoter accessibility is consistent during disease initiation and progression, at distal sites chromatin accessibility is variable enabling transcription factors (TFs) binding patterns that are differently activated in different patients and disease stages. We identify consistent progression-related chromatin alterations during the progression to CRPC. By studying the TF binding patterns, we demonstrate the activation and suppression of androgen receptor-driven regulatory programs during PC progression and identify complementary TF regulatory modules characterized by e.g. MYC and glucocorticoid receptor. By correlation analysis we assign at least one putative regulatory region for 62% of genes and 85% of proteins differentially expressed during prostate cancer progression. Taken together, our analysis of the chromatin landscape in PC identifies putative regulatory elements for the majority of cancer-associated genes and characterizes their impact on the cancer phenotype.

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Prostate cancer reactivates developmental epigenomic programs during metastatic progression

Cited by 182 publications

References 93 publications

Pioneer of prostate cancer: past, present and the future of FOXA1

Pioneer of prostate cancer: past, present and the future of FOXA1

Enhancer-associated H3K4 methylation safeguards in vitro germline competence

Chromatin accessibility analysis uncovers regulatory element landscape in prostate cancer progression

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