N-Myc–mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer

Berger, Adeline; Brady, Nicholas J.; Bareja, Rohan; Robinson, Brian D.; Conteduca, Vincenza; Augello, Michael A.; Puca, Loredana; Ahmed, Adnan; Dardenne, Étienne; Lü, Xiaodong; Hwang, Inah; Bagadion, Alyssa; Sboner, Andrea; Elemento, Olivier; Paik, Jihye; Yu, Jindan; Barbieri, Christopher E.; Dephoure, Noah; Beltran, Himisha; Rickman, David S.

doi:10.1172/jci127961

Cited by 124 publications

(111 citation statements)

References 104 publications

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“…2c, d), and (ii) MYCN and EZH2 ( Fig. 2d), which have been linked with progression to CRPC with neuroendocrine features (CRPC-NE) [8][9][10][11][12] . Silencing MUC1-C in LNCaP-AI cells resulted in the downregulation of BRN2 mRNA levels ( Fig.…”

Section: Resultsmentioning

confidence: 92%

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MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer

et al. 2020

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Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC, but its specific role is unknown. Here, we demonstrate that upregulation of MUC1-C in androgen-dependent PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor. MUC1-C activates a MYC→BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP) linked to NEPC progression. Moreover, MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, suggesting a potential therapeutic approach for CRPC and NEPC. In PC tissues, MUC1 expression associates with suppression of AR signaling and increases in BRN2 expression and NEPC score. These results highlight MUC1-C as a master effector of lineage plasticity driving progression to NEPC.

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Section: Resultsmentioning

confidence: 92%

“…NEPC has also been linked to the upregulation of MYCN and the Polycomb Repressive Complex 2 (PRC2) component EZH2 (refs. [8][9][10][11][12] ). The incidence of NEPC is increasing with the widespread use of AR-targeted agents, such as enzalutamide (ENZ), for CRPC treatment 3,4 .…”

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confidence: 99%

MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer

et al. 2020

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“…51 A clinical trial also reported that some advanced prostate cancer patients with Aurora-A and N-MYC activation achieve significant clinical benefit from alisertib. 72 Moreover, Berger et al 73 uncovered a potential mechanism by which overexpressed N-MYC interacts with AR cofactors (such as FOXA1 and HOXB13). These cofactors may alter MYCN DNA binding through competition at N-MYC binding sites or by altering the chromatin accessibility.…”

Section: Mycn and Aurka Amplificationmentioning

confidence: 99%

Epigenetic modulations and lineage plasticity in advanced prostate cancer

et al. 2020

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Prostate cancer is the most common cancer and second leading cause of cancer-related death in American men. Antiandrogen therapies are part of the standard of therapeutic regimen for advanced or metastatic prostate cancers; however, patients who receive these treatments are more likely to develop castration-resistant prostate cancer (CRPC) or neuroendocrine prostate cancer (NEPC). In the development of CRPC or NEPC, numerous genetic signaling pathways have been under preclinical investigations and in clinical trials. Accumulated evidence shows that DNA methylation, chromatin integrity, and accessibility for transcriptional regulation still play key roles in prostate cancer initiation and progression. Better understanding of how epigenetic change regulates the progression of prostate cancer and the interaction between epigenetic and genetic modulators driving NEPC may help develop a better risk stratification and more effective treatment regimens for prostate cancer patients.

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“…Current studies support that NEPC tumors arise clonally from prostate adenocarcinoma (PCA) [7], accompanying with a phenotypic transition from acini epithelial tumor cells to NE-like tumor cells [8]. This lineage transition enables tumor cells to evade androgen receptor (AR) pathway inhibitors such as enzalutamide by shedding their dependence on the AR pathway [4,9]. Consequently, tumors develop resistant to the traditional androgen dependent therapy (ADT) and thus became one subtype of castration-resistant prostate cancer (CRPC), leading to the most lethal stages of this disease [10,11].…”

Section: Introductionmentioning

confidence: 94%

“…In the last decade, the molecular features of NEPC have gradually come to light, including genomic loss of RB1 and TP53 [12], and amplification of MYCN [9,13,14]. In addition, reprogramming to an NEPC state is also linked to overexpression of neural progenitor-associated genes such as SOX2 [5,15], MYCN [9,13,14], EZH2 [16], POU3F2 [17], FOXA2 [18,19] and SIAH2 [19]. Many NEPC drivers such as SOX2 and MYCN have also been reported to be es-sential for maintaining cell stemness [20,21], raising the possibility that the emergence of NEPC is associated with acquisition of stem-like properties.…”

Section: Introductionmentioning

confidence: 99%

Single-cell analysis supports a luminal-neuroendocrine trans-differentiation in human prostate cancer

Dong

Miao

Wang

et al. 2020

Preprint

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Neuroendocrine prostate cancer is one of the most aggressive subtypes of prostate tumor. Although much progress has been made in understanding the development of neuroendocrine prostate cancer, the cellular architecture associated with neuroendocrine differentiation in human prostate cancer remain incompletely understood. Here, we use single-cell RNA sequencing to profile the transcriptomes of 21,292 cells from needle biopsies of 6 castration-resistant prostate cancers. Our analyses reveal that all neuroendocrine tumor cells display a luminal-like epithelial phenotype. In particular, lineage trajectory analysis suggests that focal neuroendocrine differentiation exclusively originate from luminal-like malignant cells rather than basal compartment. Further tissue microarray analysis validates the generality of the luminal phenotype of neuroendocrine cells. Moreover, we uncover neuroendocrine differentiation-associated gene signatures that may help us to further explore novel intrinsic molecular mechanisms deriving neuroendocrine prostate cancer.In summary, our single-cell study provides direct evidence into the cellular states underlying neuroendocrine transdifferentiation in human prostate cancer.

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N-Myc–mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer

Cited by 124 publications

References 104 publications

MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer

MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer

Epigenetic modulations and lineage plasticity in advanced prostate cancer

Single-cell analysis supports a luminal-neuroendocrine trans-differentiation in human prostate cancer

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