Amplitude modulation of androgen signaling by c-MYC

Ni, Min; Chen, Yiwen; Teng, Fei; Li, Dan; Lim, Elgene; Liu, X. Shirley; Brown, Myles

doi:10.1101/gad.209569.112

Cited by 83 publications

(88 citation statements)

References 42 publications

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“…On the other hand, even without coexisting in the same complex, PCGEM1-dependent activation of c-Myc and AR can enhance the cross talk between these two transcriptional programs. It has previously been reported that AR is able to induce the expression of c-Myc, in turn reinforcing amplification of the AR-transcriptional signals (24). The c-Myc induction by AR can also confer hormone-independent growth of prostate cancer cells (25,26).…”

Section: Discussionmentioning

confidence: 98%

A long noncoding RNA connects c-Myc to tumor metabolism

Hung

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

268

212

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Long noncoding RNAs (lncRNAs) have been implicated in a variety of physiological and pathological processes, including cancer. In prostate cancer, prostate cancer gene expression marker 1 (PCGEM1) is an androgen-induced prostate-specific lncRNA whose overexpression is highly associated with prostate tumors. PCGEM1's tumorigenic potential has been recently shown to be in part due to its ability to activate androgen receptor (AR). Here, we report a novel function of PCGEM1 that provides growth advantages for cancer cells by regulating tumor metabolism via c-Myc activation. PCGEM1 promotes glucose uptake for aerobic glycolysis, coupling with the pentose phosphate shunt to facilitate biosynthesis of nucleotide and lipid, and generates NADPH for redox homeostasis. We show that PCGEM1 regulates metabolism at a transcriptional level that affects multiple metabolic pathways, including glucose and glutamine metabolism, the pentose phosphate pathway, nucleotide and fatty acid biosynthesis, and the tricarboxylic acid cycle. The PCGEM1-mediated gene regulation takes place in part through AR activation, but predominantly through c-Myc activation, regardless of hormone or AR status. Significantly, PCGEM1 binds directly to target promoters, physically interacts with c-Myc, promotes chromatin recruitment of c-Myc, and enhances its transactivation activity. We also identified a c-Myc binding domain on PCGEM1 that contributes to the PCGEM1-dependent c-Myc activation and target induction. Together, our data uncover PCGEM1 as a key transcriptional regulator of central metabolic pathways in prostate cancer cells. By being a coactivator for both c-Myc and AR, PCGEM1 reprograms the androgen network and the central metabolism in a tumor-specific way, making it a promising target for therapeutic intervention.L ong noncoding RNAs (lncRNAs) have recently drawn increasing attention as important players in physiological and pathological processes. In cancer, aberrant expression and mutations of lncRNAs can contribute to tumor development and progression by promoting proliferation, invasion, metastasis, and survival (1-3). LncRNAs thus may serve as diagnostic biomarkers and therapeutic targets for cancer. LncRNAs function at several levels of cellular processes, and the majority thus far studied are involved in gene regulation either at the transcriptional or posttranscriptional level (4). At the transcriptional level, lncRNA can serve as a chaperon or scaffold to deliver transcriptional factor to the chromatin site, to modulate the chromatin conformation by recruiting histone-modifying complexes, and to connect distal gene-regulatory elements together to effectively modulate the transcription of the targeted loci (4).Prostate cancer gene expression marker 1 (PCGEM1) is a prostate tissue-specific lncRNA highly associated with prostate cancer (5). Over 80% of patient specimens show elevated levels (5), and the occurrence of PCGEM1 overexpression seems to be significantly higher in African-American patients, whose population has the highest pr...

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Section: Discussionmentioning

confidence: 98%

A long noncoding RNA connects c-Myc to tumor metabolism

Hung

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

268

212

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“…In the MDA-MB-453 molecular apocrine breast cancer cell line, there is a high overlap of FOXA1 and AR DNA-binding sites, particularly near androgen-regulated genes (Ni et al 2011, Robinson et al 2011. Furthermore, FOXA1 ablation reduces MDA-MB-453 colony formation (Robinson et al 2011) and blocks androgen induction of the oncogenic transcription factor MYC (Ni et al 2013). In the absence of AR activation in an ERa-negative breast cancer context, FOXA1 interacts with TCF7L2 on DNA to repress AR target genes, whereas upon hormone stimulation, AR replaces TCF7L2 in the FOXA1 complex, leading to induction of gene transcription ( Fig.…”

Section: Ar Foxa1 and Her2mentioning

confidence: 99%

“…1B), which are required for androgen-induced growth of these cells (Ni et al 2011). DHT-induced HER2 signalling also induces PI3K/AKT pathway activation, in turn leading to phosphorylation and degradation of MAD1 (MXD1), which disrupts the MAD1-MAX complex (Ni et al 2013). This allows MAX to interact with MYC, also directly induced by DHT via an AR-FOXA1 interaction (Fig.…”

Section: Ar Foxa1 and Her2mentioning

confidence: 99%

“…In the absence of AR activation in an ERa-negative breast cancer context, FOXA1 interacts with TCF7L2 on DNA to repress AR target genes, whereas upon hormone stimulation, AR replaces TCF7L2 in the FOXA1 complex, leading to induction of gene transcription ( Fig. 1B; Ni et al 2013). In ERa-negative MDA-MB-453 cells, androgens induce expression of WNT7B and HER3, leading to activation of the Wnt/b-catenin and HER2 signalling pathways (Fig.…”

Section: Ar Foxa1 and Her2mentioning

confidence: 99%

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Complexities of androgen receptor signalling in breast cancer

McNamara¹,

Moore²,

Hickey³

et al. 2014

Endocrine-Related Cancer

123

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While the clinical benefit of androgen-based therapeutics in breast cancer has been known since the 1940s, we have only recently begun to fully understand the mechanisms of androgen action in breast cancer. Androgen signalling pathways can have either beneficial or deleterious effects in breast cancer depending on the breast cancer subtype and intracellular context. This review discusses our current knowledge of androgen signalling in breast cancer, including the relationship between serum androgens and breast cancer risk, the prognostic significance of androgen receptor (AR) expression in different breast cancer subtypes and the downstream molecular pathways mediating androgen action in breast cancer cells. Intracrine androgen metabolism has also been discussed and proposed as a potential mechanism that may explain some of the reported differences regarding dichotomous androgen actions in breast cancers. A better understanding of AR signalling in this disease is critical given the current resurgence in interest in utilising contemporary AR-directed therapies for breast cancer and the need for biomarkers that will accurately predict clinical response.

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“…forms heterodimers with MAX that sequentially access transcriptional sites in a cell proliferation direction (Zhu et al 2008, Ni et al 2013; (3) AR induces dissociation of repressor transcription factor 7-like 2 (TCF7L2) from the pioneer transcription factor of AR, FOXA1, promoting AR target gene MYC transcription with mitogenic action (Ni et al 2013). There is a positive feed-forward loop involving MYC in the regulation of androgendependent transcription in ER-negative HER2-positive BC subtype; (4) AR induces ErbB2 expression, which activates ERK.…”

Section: :10mentioning

confidence: 99%

Androgen receptor signaling pathways as a target for breast cancer treatment

Pietri¹,

Conteduca²,

Andreis³

et al. 2016

Endocrine-Related Cancer

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The androgen receptor (AR) is a ligand-dependent transcription factor, and its effects on breast range from physiological pubertal development and age-related modifications to cancer onset and proliferation. The prevalence of AR in early breast cancer is around 60%, and AR is more frequently expressed in ER-positive than in ER-negative tumors. We offer an overview of AR signaling pathways in different breast cancer subtypes, providing evidence that its oncogenic role is likely to be different in distinct biological and clinical scenarios. In particular, in ER-positive breast cancer, AR signaling often antagonizes the growth stimulatory effect of ER signaling; in triple-negative breast cancer (TNBC), AR seems to drive tumor progression (at least in luminal AR subtype of TNBC with a gene expression profile mimicking luminal subtypes despite being negative to ER and enriched in AR expression); in HER2-positive breast cancer, in the absence of ER expression, AR signaling has a proliferative role. These data represent the rationale for AR-targeting treatment as a potentially new target therapy in breast cancer subset using androgen agonists in some AR-positive/ER-positive tumors, AR antagonists in triple-negative/ AR-positive tumors and in combination with anti-HER2 agents or with other signaling pathways inhibitors (including PI3K/MYC/ERK) in HER2-positive/AR-positive tumors. Only the ongoing and future prospective clinical trials will allow us to establish which agents are the best option in every specific condition, keeping in mind that there is evidence of opposite androgens and AR agonist/antagonist drug effects on cell proliferation particularly in AR-positive/ER-positive tumors.

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Amplitude modulation of androgen signaling by c-MYC

Cited by 83 publications

References 42 publications

A long noncoding RNA connects c-Myc to tumor metabolism

A long noncoding RNA connects c-Myc to tumor metabolism

Complexities of androgen receptor signalling in breast cancer

Androgen receptor signaling pathways as a target for breast cancer treatment

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