MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets

Qiu, Xintao; Boufaied, Nadia; Hallal, Tarek; Feit, Avery; Polo, Anna de; Luoma, Adrienne; Larocque, Janie; Zadra, Giorgia; Xie, Yingtian; Gu, Shengqing; Tang, Qin; Zhang, Yi; Syamala, Sudeepa; Seo, Ji-Heui; Bell, Connor; O’Connor, Edward; Liu, Yang; Schaeffer, Edward M.; Karnes, R. Jeffrey; Weinmann, Sheila; Davicioni, Elai; Cejas, Paloma; Ellis, Leigh; Loda, Massimo; Wucherpfennig, Kai W.; Pomerantz, Mark; Spratt, Daniel E.; Corey, Eva; Freedman, Matthew L.; Liu, X. Shirley; Brown, Myles; Long, Henry W.; Labbé, David P.

doi:10.1101/2021.04.23.441016

Cited by 7 publications

(6 citation statements)

References 73 publications

(87 reference statements)

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“…Finally, aggressive PC is characterized by amplification of MYC , which is the most frequent genomic alteration in NEPCs ( Rebello et al., 2021 ). MYC antagonizes AR transcriptional programs pioneered by FOXA1, underscoring the interdependence of PC on this handful of TFs ( Hawksworth et al., 2010 ; Qiu et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

FOXA1 regulates alternative splicing in prostate cancer

et al. 2022

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Section: Introductionmentioning

confidence: 99%

FOXA1 regulates alternative splicing in prostate cancer

et al. 2022

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“…considering the coordinated action of c-myc and ar in Pca development (64,65), the effect of anti-androgens was evaluated. The results showed an increased expression of p-c-myc with bicalutamide, enzalutamide and apalutamide exposure of LNCaP-WT cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

STEAP1 regulation and its influence modulating the response of LNCaP prostate cancer cells to bicalutamide, enzalutamide and apalutamide

et al. 2023

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anti-androgen drugs are the standard pharmacological therapies for treatment of non-metastatic prostate cancer (Pca). However, the response of Pca cells may depend on the anti-androgen used and often patients become resistant to treatment. Thus, studying how the anti-androgen drugs affect oncogenes expression and action and the identification of the best strategy for combined therapies are essential to improve the efficacy of treatments. The Six Transmembrane epithelial antigen of the Prostate 1 (STeaP1) is an oncogene associated with Pca progression and aggressiveness, although its relationship with the androgen receptor signaling remains to be elucidated. The present study aimed to evaluate the effect of anti-androgens in regulating STeaP1 expression and investigate whether silencing STeaP1 can make Pca cells more sensitive to anti-androgen drugs. For this purpose, wild-type and STeaP1 knockdown lncaP cells were exposed to bicalutamide, enzalutamide and apalutamide. Bicalutamide decreased the expression of STeaP1, but enzalutamide and apalutamide increased its expression. However, decreased cell proliferation and increased apoptosis was observed in response to all drugs. overall, the cellular and molecular effects were similar between lncaP wild-type and lncaP-STeaP1 knockdown cells, except for c-myc expression levels, where a cumulative effect between anti-androgen treatment and STeaP1 knockdown was observed. The effect of STeaP1 knockdown alone or combined with anti-androgens in c-myc levels is required to be addressed in future studies.

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“…Similarly, AR-directed therapies suppress AR activity in patients with metastatic PCa, such that resistant tumors are less dependent on AR for growth and survival [39]. Thus, histologically and clinically aggressive tumors may reflect a causal link between increased MYC activity and decreased but persistent AR activity, due in part to a transcriptional pause-release effect that accounts for lower AR tumors having worse clinical outcomes [4, 40]. A logical future study will be to broadly assess the metabolic and lipogenic ramifications of differential AR/MYC status.…”

Section: Discussionmentioning

confidence: 99%

Progression of prostate cancer reprograms MYC-mediated lipid metabolism via lysine methyltransferase 2A

Whitlock¹,

White²,

Capaldo³

et al. 2022

Preprint

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Background The activities of MYC, the androgen receptor, and its associated pioneer factors demonstrate substantial reprogramming between early and advanced prostate cancer. Although previous studies have shown a shift in cellular metabolic requirements associated with prostate cancer progression, the epigenetic regulation of these processes is incompletely described. Here, we have integrated chromatin immunoprecipitation sequencing (ChIP-seq) and whole-transcriptome sequencing to identify novel regulators of metabolism in advanced prostate tumors characterized by elevated MYC activity. Results Using ChIP-seq against MYC, HOXB13, and AR in LNCaP cells, we observed redistribution of co-bound sites suggestive of differential KMT2A activity as a function of MYC expression. In a cohort of 177 laser-capture microdissected foci of prostate tumors, KMT2A expression was positively correlated with MYC activity, AR activity, and HOXB13 expression, but decreased with tumor grade severity. However, KMT2A expression was negatively correlated with these factors in 25 LuCaP patient-derived xenograft models of advanced prostate cancer and 99 laser-capture microdissected foci of metastatic castration-resistant prostate cancer. Stratified by KMT2A expression, ChIP-seq against AR and HOXB13 in 15 LuCaP patient-derived xenografts showed an inverse association with sites involving genes implicated in lipid metabolism, including the arachidonic acid metabolic enzyme PLA2G4F. LuCaP patient-derived xenograft models grown as organoids recapitulated the inverse association between KMT2A expression and fluorine-18 labeled arachidonic acid uptake in vitro. Conclusions Our study demonstrates that the epigenetic activity of transcription factor oncogenes exhibits a shift during prostate cancer progression with distinctive phenotypic effects on metabolism. These epigenetically driven changes in lipid metabolism may serve as novel targets for the development of novel imaging agents and therapeutics.

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MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets

Cited by 7 publications

References 73 publications

FOXA1 regulates alternative splicing in prostate cancer

FOXA1 regulates alternative splicing in prostate cancer

STEAP1 regulation and its influence modulating the response of LNCaP prostate cancer cells to bicalutamide, enzalutamide and apalutamide

Progression of prostate cancer reprograms MYC-mediated lipid metabolism via lysine methyltransferase 2A

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