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; Alahmadi, Walaa; Larocque, Janie; Zadra, Giorgia; Xie, Yingtian; Gu, Shengqing Stan; 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; Morrissey, Colm; 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:10.1038/s41467-022-30257-z

Cited by 77 publications

(59 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Altogether, our data demonstrated that the combination of EZH2i and BETi is a rational pharmacological strategy to target c-myc in late stage mCRPC cells that are almost unresponsive to both GSK126 and JQ1 when used as a single drug treatment. From a clinical point of view our finding is relevant, considering that divergent AR (low) and MYC (high) transcriptional signatures predisposes patients to fail standard-of-care therapies and progress to the mCRPC stage 52 . Therefore, considering the heterogeneity of late stage mCRPC disease, appropriate patient selection through molecular diagnostics may be necessary to identify the right population that might benefit of the proposed myc-targeting strategy to maximise the therapeutic outcome.…”

Section: Discussionmentioning

confidence: 88%

Simultaneous administration of EZH2 and BET inhibitors inhibits proliferation and clonogenic ability of metastatic prostate cancer cells

Negri

Marozzi

Trisciuoglio

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

Androgen deprivation therapy (ADT) is a common treatment for recurrent prostate cancer (PC). However, after a certain period of responsiveness, ADT resistance occurs virtually in all patients and the disease progresses to lethal metastatic castration-resistant prostate cancer (mCRPC). Aberrant expression and function of the epigenetic modifiers EZH2 and BET over activates c-myc, an oncogenic transcription factor critically contributing to mCRPC. In the present work, we tested, for the first time, the combination of an EZH2 inhibitor with a BET inhibitor in metastatic PC cells. The combination outperformed single drugs in inhibiting cell viability, cell proliferation and clonogenic ability, and concomitantly reduced both c-myc and NF-kB expression. Although these promising results will warrant further in vivo validation, they represent the first step to establishing the rationale that the proposed combination might be suitable for mCRPC treatment, by exploiting molecular targets different from androgen receptor.

show abstract

Section: Discussionmentioning

confidence: 88%

Simultaneous administration of EZH2 and BET inhibitors inhibits proliferation and clonogenic ability of metastatic prostate cancer cells

Negri

Marozzi

Trisciuoglio

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…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

et al. 2022

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 77 publications

References 76 publications

Simultaneous administration of EZH2 and BET inhibitors inhibits proliferation and clonogenic ability of metastatic prostate cancer cells

Simultaneous administration of EZH2 and BET inhibitors inhibits proliferation and clonogenic ability of metastatic prostate cancer cells

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

Contact Info

Product

Resources

About