Exploiting the tumor-suppressive activity of the androgen receptor by CDK4/6 inhibition in castration-resistant prostate cancer

Han, Wanting; Liu, Mingyu; Han, Dong; Toure, Anthia A.; Li, Muqing; Besschetnova, Anna; Wang, Zifeng; Patalano, Susan; Macoska, Jill A.; Lam, Hung‐Ming; Corey, Eva; He, Housheng Hansen; Gao, Shuai; Balk, Steven P.; Cai, Changmeng

doi:10.1016/j.ymthe.2022.01.039

Cited by 20 publications

(10 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The growth-suppressive nature of AR signaling in normal cells has been a well-known but poorly understood phenomenon at a mechanistic level 33,34 . Others have proposed that a transcriptional repression function of AR mediates this activity 35,36 . Our data showing that direct activation of ARE-containing chromatin regions engages the growth-suppressive effects of AR suggests that selective, context-dependent transactivation is responsible.…”

Section: Discussionmentioning

confidence: 99%

Canonical AREs are tumor suppressive regulatory elements in the prostate

Augello,

Chen,

Liu

et al. 2024

Preprint

View full text Add to dashboard Cite

The androgen receptor (AR) is the central determinant of prostate tissue identity and differentiation, controlling normal, growth-suppressive prostate-specific gene expression. It is also a key driver of prostate tumorigenesis, becoming hijacked to drive oncogenic transcription. However, the regulatory elements determining the execution of the growth suppressive AR transcriptional program, and whether this can be reactivated in prostate cancer (PCa) cells remains unclear. Canonical androgen response element (ARE) motifs are the classic DNA binding element for AR. Here, we used a genome-wide strategy to modulate regulatory elements containing AREs to define distinct AR transcriptional programs. We find that activation of these AREs is specifically associated with differentiation and growth suppressive transcription, and this can be reactivated to cause death in AR+ PCa cells. In contrast, repression of AREs is well tolerated by PCa cells, but deleterious to normal prostate cells. Finally, gene expression signatures driven by ARE activity are associated with improved prognosis and luminal phenotypes in human PCa patients. This study demonstrates that canonical AREs are responsible for a normal, growth-suppressive, lineage-specific transcriptional program, that this can be reengaged in PCa cells for potential therapeutic benefit, and genes controlled by this mechanism are clinically relevant in human PCa patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Canonical AREs are tumor suppressive regulatory elements in the prostate

Augello,

Chen,

Liu

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…More importantly, we fully characterized this AR reprogramming and revealed that one critical outcome is the distinct activation of genes mediating DNA replication and damage repair pathways, which may allow CRPC cells to become resistant to genotoxic stress. Interestingly, our previous studies indicated that the combination of AR overexpression and high-dose androgens can transcriptionally suppress DNA replication genes, which provides a molecular basis for the high-dose testosterone treatment in CRPC ( 5 , 44 , 45 ). Although we did not focus on this non-physiological condition in this study, our data showed that the activation of DNA damage repair genes almost disappeared under AR high /DHT high condition (see Figures 2C and 6B ), which may be contributed by this transcriptional repression mechanism.…”

Section: Discussionmentioning

confidence: 99%

Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2

Labaf

Ting

et al. 2022

Front. Oncol.

Self Cite

View full text Add to dashboard Cite

Elevated androgen receptor (AR) expression is a hallmark of castration-resistant prostate cancer (CRPC) and contributes to the restoration of AR signaling under the conditions of androgen deprivation. However, whether overexpressed AR alone with the stimulation of castrate levels of androgens can be sufficient to induce the reprogramming of AR signaling for the adaptation of prostate cancer (PCa) cells remains unclear. In this study, we used a PCa model with inducible overexpression of AR to examine the acute effects of AR overexpression on its cistrome and transcriptome. Our results show that overexpression of AR alone in conjunction with lower androgen levels can rapidly redistribute AR chromatin binding and activates a distinct transcription program that is enriched for DNA damage repair pathways. Moreover, using a recently developed bioinformatic tool, we predicted the involvement of EZH2 in this AR reprogramming and subsequently identified a subset of AR/EZH2 co-targeting genes, which are overexpressed in CRPC and associated with worse patient outcomes. Mechanistically, we found that AR-EZH2 interaction is impaired by the pre-castration level of androgens but can be recovered by the post-castration level of androgens. Overall, our study provides new molecular insights into AR signaling reprogramming with the engagement of specific epigenetic factors.

show abstract

“…Notably, the induction of ERRFI1 mRNA and recruitment of AR by SAL was recently also described for VCaP cells [ 30 ]. Furthermore, SAL was shown to enhance ERRFI1 mRNA levels in patient-derived mouse xenografts treated with vehicle or high-dose androgen [ 31 ] ( supplemental Figure S6 ). Based on the high degree of tumor heterogeneity of PCa [ 27 ], a generalized conclusion cannot be drawn.…”

Section: Discussionmentioning

confidence: 99%

Androgen-Induced MIG6 Regulates Phosphorylation of Retinoblastoma Protein and AKT to Counteract Non-Genomic AR Signaling in Prostate Cancer Cells

et al. 2022

View full text Add to dashboard Cite

The bipolar androgen therapy (BAT) includes the treatment of prostate cancer (PCa) patients with supraphysiological androgen level (SAL). Interestingly, SAL induces cell senescence in PCa cell lines as well as ex vivo in tumor samples of patients. The SAL-mediated cell senescence was shown to be androgen receptor (AR)-dependent and mediated in part by non-genomic AKT signaling. RNA-seq analyses compared with and without SAL treatment as well as by AKT inhibition (AKTi) revealed a specific transcriptome landscape. Comparing the top 100 genes similarly regulated by SAL in two human PCa cell lines that undergo cell senescence and being counteracted by AKTi revealed 33 commonly regulated genes. One gene, ERBB receptor feedback inhibitor 1 (ERRFI1), encodes the mitogen-inducible gene 6 (MIG6) that is potently upregulated by SAL, whereas the combinatory treatment of SAL with AKTi reverses the SAL-mediated upregulation. Functionally, knockdown of ERRFI1 enhances the pro-survival AKT pathway by enhancing phosphorylation of AKT and the downstream AKT target S6, whereas the phospho-retinoblastoma (pRb) protein levels were decreased. Further, the expression of the cell cycle inhibitor p15INK4b is enhanced by SAL and ERRFI1 knockdown. In line with this, cell senescence is induced by ERRFI1 knockdown and is enhanced slightly further by SAL. Treatment of SAL in the ERRFI1 knockdown background enhances phosphorylation of both AKT and S6 whereas pRb becomes hypophosphorylated. Interestingly, the ERRFI1 knockdown does not reduce AR protein levels or AR target gene expression, suggesting that MIG6 does not interfere with genomic signaling of AR but represses androgen-induced cell senescence and might therefore counteract SAL-induced signaling. The findings indicate that SAL treatment, used in BAT, upregulates MIG6, which inactivates both pRb and the pro-survival AKT signaling. This indicates a novel negative feedback loop integrating genomic and non-genomic AR signaling.

show abstract

Exploiting the tumor-suppressive activity of the androgen receptor by CDK4/6 inhibition in castration-resistant prostate cancer

Cited by 20 publications

References 70 publications

Canonical AREs are tumor suppressive regulatory elements in the prostate

Canonical AREs are tumor suppressive regulatory elements in the prostate

Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2

Androgen-Induced MIG6 Regulates Phosphorylation of Retinoblastoma Protein and AKT to Counteract Non-Genomic AR Signaling in Prostate Cancer Cells

Contact Info

Product

Resources

About