CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis

Augello, Michael A.; D, Liu; Deonarine, Lesa D.; Robinson, Brian D.; Huang, Dennis; Stelloo, Suzan; Blattner, Mirjam; Doane, Ashley S.; Wong, Elissa W.P.; Chen, Yu; Rubin, Mark A.; Beltran, Himisha; Elemento, Olivier; Bergman, Andries M.; Zwart, Wilbert; Sboner, Andrea; Dephoure, Noah; Barbieri, Christopher E.

doi:10.1016/j.ccell.2019.03.001

Cited by 85 publications

(94 citation statements)

References 82 publications

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“…Therefore, the increase in metastasis upon CHD1 loss was observed irrespective of the AR and PTEN status. Further studies are required to determine whether the prognostic role of CHD1 loss is independent of the AR signaling activity and PTEN status in patients since recent publications indicate a close relationship between CHD1 and AR, CHD1 and resistance to AR-targeted therapy as well as CHD1 and PTEN [21][22][23][24]. In a parallel study including 4986 patients with known CHD1 and PTEN status we determined the prognostic role of CHD1 loss in PTEN-wildtype vs -deleted patient subsets (Oh-Hohenhorst et al, in preparation).…”

Section: Discussionmentioning

confidence: 99%

CHD1 loss negatively influences metastasis-free survival in R0-resected prostate cancer patients and promotes spontaneous metastasis in vivo

et al. 2021

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The outcome of prostate cancer (PCa) patients is highly variable and depends on whether or not distant metastases occur. Multiple chromosomal deletions have been linked to early tumor marker PSA recurrence (biochemical relapse, BCR) after radical prostatectomy (RP), but their potential role for distant metastasis formation is largely unknown. Here, we specifically analyzed whether deletion of the tumor suppressor CHD1 (5q21) influences the post-surgical risk of distant metastasis and whether CHD1 loss directly contributes to metastasis formation in vivo. By considering >6800 patients we found that the CHD1 deletion negatively influences metastasis-free survival in R0 patients (HR: 2.32; 95% CI: 1.61, 3.33; p < 0.001) independent of preoperative PSA, pT stage, pN status, Gleason Score, and BCR. Moreover, CHD1 deletion predicts shortened BCR-free survival in pT2 patients and cancer-specific survival in all patients. In vivo, CHD1 loss increases spontaneous pulmonary metastasis formation in two distinct PCa models coupled with a higher number of multicellular colonies as compared to single-cell metastases. Transcriptome analyses revealed down-regulation of the PCa-specific metastasis suppressor and TGFβ signaling regulator PMEPA1 after CHD1 depletion in both tested PCa models. CHD1 loss increases the risk of postoperative metastasis in R0-resected PCa patients and promotes spontaneous metastasis formation in vivo.

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Section: Discussionmentioning

confidence: 99%

CHD1 loss negatively influences metastasis-free survival in R0-resected prostate cancer patients and promotes spontaneous metastasis in vivo

et al. 2021

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“…PCa is generally a slow proliferating tumor with few key mutations and genetic alterations that are commonly found in all patients such as TMPRSS-ERG, SPOP, FOXA1, PTEN [31,32]. Loss of CHD1 heterozygosity is found in 15% PCa cases and drives prostate-specific cancer growth in transgenic mice [33]. PNPCa contains a frameshift mutation in the tumor suppressor gene CHD1; since CHD1 deletions frequently co-occur with SPOP mutations [34], we compared the transcriptome of PNPCa PDX to signatures of CHD1homozygous deletion cases and SPOP-mutated cases, which frequently occur together, along with other subtypes (ETS rearrangements and FOXA1 mutations).…”

Section: Discussionmentioning

confidence: 99%

Patient-derived xenografts and organoids model therapy response in prostate cancer

Karkampouna

Manna

Filippo

et al. 2020

Preprint

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Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe a novel androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa).RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbours BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modelled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX-and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds.This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds. Conflict of interest and Disclosure Statement:The authors declare no conflict of interest.

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“…It is important to note that loss of CHD1, observed in ~15% of primary prostate cancer cases, is rarely deleted in other cancer types, suggesting a prostate-specific role as a tumor suppressor of prostate tumorigenesis [614]. Initial studies have provided evidence that, in contrast to PTEN prostate conditional models, which generate highly invasive adenocarcinomas, homozygous deletion of CHD1 in prostate progenitors causes only low-grade PIN lesions [148].…”

Section: Prostate Cancer Stem Cellsmentioning

confidence: 99%

“…Initial studies have provided evidence that, in contrast to PTEN prostate conditional models, which generate highly invasive adenocarcinomas, homozygous deletion of CHD1 in prostate progenitors causes only low-grade PIN lesions [148]. A recent study provided evidence, through the analysis of prostate organoids, that CHD1 loss drives prostate tumorigenesis by modifying AR binding at the level of lineage-specific enhancers and, particularly, shifts AR chromatin occupancy to trigger HOXB13-directed oncogenic transcription, in a context also dependent on the function of other tumor suppressors [614].…”

Section: Prostate Cancer Stem Cellsmentioning

confidence: 99%

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

2019

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Prostate cancer is the most frequent nonskin cancer and second most common cause of cancer-related deaths in man. Prostate cancer is a clinically heterogeneous disease with many patients exhibiting an aggressive disease with progression, metastasis, and other patients showing an indolent disease with low tendency to progression. Three stages of development of human prostate tumors have been identified: intraepithelial neoplasia, adenocarcinoma androgen-dependent, and adenocarcinoma androgen-independent or castration-resistant. Advances in molecular technologies have provided a very rapid progress in our understanding of the genomic events responsible for the initial development and progression of prostate cancer. These studies have shown that prostate cancer genome displays a relatively low mutation rate compared with other cancers and few chromosomal loss or gains. The ensemble of these molecular studies has led to suggest the existence of two main molecular groups of prostate cancers: one characterized by the presence of ERG rearrangements (~50% of prostate cancers harbor recurrent gene fusions involving ETS transcription factors, fusing the 5′ untranslated region of the androgen-regulated gene TMPRSS2 to nearly the coding sequence of the ETS family transcription factor ERG) and features of chemoplexy (complex gene rearrangements developing from a coordinated and simultaneous molecular event), and a second one characterized by the absence of ERG rearrangements and by the frequent mutations in the E3 ubiquitin ligase adapter SPOP and/or deletion of CDH1, a chromatin remodeling factor, and interchromosomal rearrangements and SPOP mutations are early events during prostate cancer development. During disease progression, genomic and epigenomic abnormalities accrued and converged on prostate cancer pathways, leading to a highly heterogeneous transcriptomic landscape, characterized by a hyperactive androgen receptor signaling axis.

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CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis

Abstract: Graphical AbstractHighlights d CHD1 acts as a prostate-specific tumor suppressor in vivo d CHD1 regulates AR occupancy at a subset of lineage-specific enhancers d Loss of CHD1 redistributes the AR cistrome to favor oncogenic AR-driven pathways

Cited by 85 publications

References 82 publications

CHD1 loss negatively influences metastasis-free survival in R0-resected prostate cancer patients and promotes spontaneous metastasis in vivo

CHD1 loss negatively influences metastasis-free survival in R0-resected prostate cancer patients and promotes spontaneous metastasis in vivo

Patient-derived xenografts and organoids model therapy response in prostate cancer

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

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