Androgen receptor and its splice variant, AR-V7, differentially induce mRNA splicing in prostate cancer cells

Rana, Manjul; Dong, Jianrong; Robertson, Matthew J.; Coarfa, Cristian; Weigel, Nancy L.

doi:10.1038/s41598-021-81164-0

Cited by 12 publications

(13 citation statements)

References 47 publications

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“…In addition to their role in transcriptional regulation, nuclear receptors, including the AR, have been shown to recruit coregulators that influence alternative splicing of target genes [ 57 , 58 ]. This is particularly relevant to PCa where full-length AR and the pathogenic truncated variant AR-v7 regulate distinct splicing networks [ 59 ]. Therefore, this study investigated the role of METTL3 on androgen-induced splicing.…”

Section: Discussionmentioning

confidence: 99%

The METTL3 RNA Methyltransferase Regulates Transcriptional Networks in Prostate Cancer

Haigh

Woodcock

Lothion-Roy

et al. 2022

Cancers

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Prostate cancer (PCa) is a leading cause of cancer-related deaths and is driven by aberrant androgen receptor (AR) signalling. For this reason, androgen deprivation therapies (ADTs) that suppress androgen-induced PCa progression either by preventing androgen biosynthesis or via AR signalling inhibition (ARSi) are common treatments. The N6-methyladenosine (m6A) RNA modification is involved in regulating mRNA expression, translation, and alternative splicing, and through these mechanisms has been implicated in cancer development and progression. RNA-m6A is dynamically regulated by the METTL3 RNA methyltransferase complex and the FTO and ALKBH5 demethylases. While there is evidence supporting a role for aberrant METTL3 in many cancer types, including localised PCa, the wider contribution of METTL3, and by inference m6A, in androgen signalling in PCa remains poorly understood. Therefore, the aim of this study was to investigate the expression of METTL3 in PCa patients and study the clinical and functional relevance of METTL3 in PCa. It was found that METTL3 is aberrantly expressed in PCa patient samples and that siRNA-mediated METTL3 knockdown or METTL3-pharmacological inhibition significantly alters the basal and androgen-regulated transcriptome in PCa, which supports targeting m6A as a novel approach to modulate androgen signalling in PCa.

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Section: Discussionmentioning

confidence: 99%

The METTL3 RNA Methyltransferase Regulates Transcriptional Networks in Prostate Cancer

Haigh

Woodcock

Lothion-Roy

et al. 2022

Cancers

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“…It is known that constitutively active AR variant (ARV7) can bind to androgen response element (ARE) motif. 30 , 31 Thus, ARV7 overexpression in PC3 cells can suppress SphK1 expression (Supporting information Figure S2E ). Moreover, DHT can inhibit SphK1 expression in PC3 cells‐expressing AR (Supporting information Figure S2F ).…”

Section: Resultsmentioning

confidence: 92%

“…Consistently, increased S1P production was observed in LNCaP treated with Enzalutamide for 24 h (Right panel, Figure S2D). It is known that constitutively active AR variant (ARV7) can bind to androgen response element (ARE) motif 30,31 . Thus, ARV7 overexpression in PC3 cells can suppress SphK1 expression (Supporting information Figure S2E).…”

Section: Resultsmentioning

confidence: 99%

The central role of Sphingosine kinase 1 in the development of neuroendocrine prostate cancer (NEPC): A new targeted therapy of NEPC

Lee

Chen

Hernández

et al. 2022

Clinical & Translational Med

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Background Neuroendocrine prostate cancer (NEPC) is often diagnosed as a sub‐type from the castration‐resistant prostate cancer (CRPC) recurred from the second generation of anti‐androgen treatment and is a rapidly progressive fatal disease. The molecular mechanisms underlying the trans‐differentiation from CRPC to NEPC are not fully characterized, which hampers the development of effective targeted therapy. Methods Bioinformatic analyses were conducted to determine the clinical correlation of sphingosine kinase 1 (SphK1) in CRPC progression. To investigate the transcriptional regulation SphK1 and neuroendocrine (NE) transcription factor genes, both chromosome immunoprecipitation and luciferase reporter gene assays were performed. To demonstrate the role of SphK1 in NEPC development, neurosphere assay was carried out along with several biomarkers determined by quantitative PCR and western blot. Furthermore, in vivo NEPC xenograft models and patient‐derived xenograft (PDX) model were employed to determine the effect of SphK1 inhibitors and target validation. Results Significant prevalence of SphK1 in NEPC development is observed from clinical datasets. SphK1 is transcriptionally repressed by androgen receptor‐RE1‐silencing transcription factor (REST) complex. Furthermore, sphingosine 1‐phosphate produced by SphK1 can modulate REST protein turnover via MAPK signaling pathway. Also, decreased REST protein levels enhance the expression of NE markers in CRPC, enabling the transition to NEPC. Finally, specific SphK1 inhibitors can effectively inhibit the growth of NEPC tumors and block the REST protein degradation in PDX. Conclusions SphK1 plays a central role in NEPC development, which offers a new target for this lethal cancer using clinically approved SphK1 inhibitors.

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“…5 I-K). Furthermore, JQ-1 also induced the transcriptional activities of nuclear factor (erythroid-derived-2)-like-2 (NFL2L2)/(NRF-2) and androgen receptor (AR), which drive a cytoprotective response (He et al, 2020) and RNA alternative splicing (Rana et al, 2021; Shah et al, 2020), respectively (Fig. 6A).…”

Section: Resultsmentioning

confidence: 99%

Pharmacological inhibition of bromodomain and extra-terminal proteins induces NRF-2-mediated inhibition of SARS-CoV-2 replication and is subject to viral antagonism

Mhlekude

Postmus

Weiner

et al. 2022

Preprint

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Inhibitors of bromodomain and extra-terminal proteins (iBETs), including JQ-1, have been suggested as potential therapeutics against SARS-CoV-2 infection. However, molecular mechanisms underlying JQ-1-induced antiviral activity and its susceptibility to viral antagonism remain incompletely understood. iBET treatment transiently inhibited infection by SARS-CoV-2 variants and SARS-CoV, but not MERS-CoV. Our functional assays confirmed JQ-1-mediated downregulation of ACE2 expression and multi-omics analysis uncovered induction of an antiviral NRF-2-mediated cytoprotective response as an additional antiviral component of JQ-1 treatment. Serial passaging of SARS-CoV-2 in the presence of JQ-1 resulted in predominance of ORF6-deficient variants. JQ-1 antiviral activity was transient in human bronchial airway epithelial cells (hBAECs) treated prior to infection and absent when administered therapeutically. We propose that JQ-1 exerts pleiotropic effects that collectively induce a transient antiviral state that is ultimately nullified by an established SARS-CoV-2 infection, raising questions on their clinical suitability in the context of COVID-19.

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Androgen receptor and its splice variant, AR-V7, differentially induce mRNA splicing in prostate cancer cells

Cited by 12 publications

References 47 publications

The METTL3 RNA Methyltransferase Regulates Transcriptional Networks in Prostate Cancer

The METTL3 RNA Methyltransferase Regulates Transcriptional Networks in Prostate Cancer

The central role of Sphingosine kinase 1 in the development of neuroendocrine prostate cancer (NEPC): A new targeted therapy of NEPC

Pharmacological inhibition of bromodomain and extra-terminal proteins induces NRF-2-mediated inhibition of SARS-CoV-2 replication and is subject to viral antagonism

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