Analysis of the androgen receptor–regulated lncRNA landscape identifies a role for ARLNC1 in prostate cancer progression

Zhang, Yajia; Pitchiaya, Sethuramasundaram; Cieślik, Marcin; Niknafs, Yashar S.; Tien, Jean C.; Hosono, Yasuyuki; Iyer, Matthew K.; Yazdani, Sahr; Subramaniam, Shruthi; Shukla, Sudhanshu; Jiang, Xia; Wang, Lisha; Liu, Tzu-Ying; Uhl, Michaël; Gawronski, Alexander; Qiao, Yuanyuan; Xiao, Lanbo; Dhanasekaran, Saravana M.; Juckette, Kristin M.; Kunju, Lakshmi P.; Cao, Xuhong; Patel, Utsav; Batish, Mona; Shukla, Girish C.; Paulsen, Michelle T.; Ljungman, Mats; Jiang, Hui; Mehra, Rohit; Backofen, Rolf; Sahinalp, Cenk; Freier, Susan M.; Watt, Andrew T.; Guo, Shuling; Wei, John T.; Feng, Felix Y.; Malik, Rohit; Chinnaiyan, Arul M.

doi:10.1038/s41588-018-0120-1

Cited by 194 publications

(142 citation statements)

References 73 publications

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“…Therefore, we focused our attention on the post‐transcriptional regulation of EGR4 by ZNF205‐AS1. Several cytoplasmic lncRNAs have been shown to regulate the stability and/or expression of target mRNAs via RNA‐RNA interaction . Therefore, we searched the interacted RNAs with ZNF205‐AS1 using IntaRNA (http://rna.informatik.uni-freiburg.de/IntaRNA/Input.jsp).…”

Section: Resultsmentioning

confidence: 99%

“…Several cytoplasmic lncRNAs have been shown to regulate the stability and/or expression of target mRNAs via RNA-RNA interaction. 27,28 Therefore, we searched the interacted RNAs with ZNF205-AS1 using IntaRNA (http://rna.informatik.uni-freiburg.de/IntaRNA/ Input.jsp). 29 Intriguingly, 3'UTR of EGR4 mRNA was identified as a direct target of ZNF205-AS1 with the binding sites at 651-723 nucleotides of ZNF205-AS1 and at 1914-1977 nucleotides of EGR4 mRNA ( Figure 3H).…”

Section: Rna Interactionmentioning

confidence: 99%

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A positive feedback loop between ZNF205‐AS1 and EGR4 promotes non‐small cell lung cancer growth

Lin

Yang

et al. 2018

J Cellular Molecular Medi

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Accumulating evidences revealed that long noncoding RNAs (lncRNAs) are frequently implicated in non‐small cell lung cancer (NSCLC). Herein, we reported the identification of a novel NSCLC‐associated functional lncRNA ZNF205 antisense RNA 1 (ZNF205‐AS1). ZNF205‐AS1 was increased in NSCLC tissues and cell lines, and associated with poor prognosis of NSCLC patients. Bioinformatics prediction, combined with experimental verification revealed that early growth response 4 (EGR4) directly bound to ZNF205‐AS1 promoter, increased the promoter activity of ZNF205‐AS1, and activated ZNF205‐AS1 transcription. Intriguingly, ZNF205‐AS1 transcript directly interacted with EGR4 mRNA, increased EGR4 mRNA stability, and up‐regulated EGR4 expression via RNA‐RNA interaction. Thus, ZNF205‐AS1 and EGR4 formed a positive feedback loop. Through regulating EGR4, ZNF205‐AS1 activated its own promoter activity. EGR4 was also increased in NSCLC and the expression of ZNF205‐AS1 was significantly positively correlated with EGR4 in NSCLC tissues. Gain‐of‐function and loss‐of‐function assays demonstrated that both ZNF205‐AS1 and EGR4 promoted NSCLC cell growth in vitro and NSCLC tumour growth in vivo. Concurrently depleting ZNF205‐AS1 and EGR4 more significantly repressed NSCLC tumour growth in vivo. Collectively, our study demonstrated that the positive feedback loop between ZNF205‐AS1 and EGR4 promotes NSCLC growth, and implied that targeting this feedback loop may be promising therapeutic strategy for NSCLC.

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Section: Resultsmentioning

confidence: 99%

Section: Rna Interactionmentioning

confidence: 99%

A positive feedback loop between ZNF205‐AS1 and EGR4 promotes non‐small cell lung cancer growth

Lin

Yang

et al. 2018

J Cellular Molecular Medi

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“…Once exposed to the male hormone androgen, AR, becomes activated, and translocates to the nucleus, where it binds to the androgen response elements (ARE) and initiate the transcriptional program [3][4][5][6][7] . Interestingly, activated AR molecules both enhance and suppress the expression of genes involved in prostate cancer progression [8][9][10][11][12][13] . This hormone-driven AR signaling is essential for development, differentiation, and normal functioning of the prostatic gland 14 .…”

Section: Introductionmentioning

confidence: 99%

Androgen Receptor Signaling Regulates the Transcriptome of Prostate Cancer Cells by Modulating Global Alternative Splicing

Shah

Gagliano

Garland

et al. 2019

Preprint

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Androgen receptor (AR), is a transcription factor and a member of a hormone receptor superfamily. AR plays a vital role in the progression of prostate cancer and is a crucial target for therapeutic interventions. While the majority of advanced-stage prostate cancer patients will initially respond to the androgen-deprivation, the disease often progresses to castrate-resistant prostate cancer (CRPC). Interestingly, CRPC tumors continue to depend on hyperactive AR signaling and will respond to potent second-line anti-androgen therapies, including bicalutamide (CASODEX Ò ) and enzalutamide (XTANDI Ò ). However, the progression-free survival rate for the CRPC patients on antiandrogen therapies is only 8 to 19 months. Hence, there is a need to understand the mechanisms underlying CRPC progression and eventual treatment resistance. Here, we have leveraged next-generation sequencing and newly developed analytical methodologies to evaluate the role of AR-signaling in regulating the transcriptome of prostate cancer cells. The genomic and pharmacologic stimulation-and inhibition-of AR activity demonstrates that AR regulates alternative splicing within cancer-relevant genes.Furthermore, by integrating transcriptomic data from in vitro experiments and in prostate cancer patients, we found that a significant number of AR-regulated splicing events are associated with tumor progression. For example, we found evidence for an inadvertent AR-antagonist mediated switch in IDH1 and PL2G2A isoform expression, which is associated with a decrease in overall survival of patients. Mechanistically, we discovered that the epithelial-specific splicing regulators (ESRP1 and ESRP2), flank many ARregulated alternatively spliced exons. And, using 2D-invasion assays, we show that the inhibition of ESRPs can suppress AR-antagonist driven tumor invasion. In conclusion, until now, AR signaling has been primarily thought to modulate transcriptome of prostate epithelial cells by inducing or suppressing gene expression. Our work provides evidence for a new mechanism by which AR alters the transcriptome of prostate cancer cells by modulating alternative splicing. As such, our work has important implications for CRPC progression and development of resistance to treatment with bicalutamide and enzalutamide.

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“…Although many lncRNAs have been demonstrated to play critical roles in cell function, only a few lncRNAs were studied in hormone signaling pathways. The Androgen receptor‐regulated lncRNA was identified as a novel therapeutic target, which maintains the positive feedback loop that potentiates androgen receptor signaling during prostate cancer progression (Zhang et al, ). The androgen‐regulated lncRNA SOCS2‐AS1 (Suppressor of cytokine signaling 2‐antisense transcript 1) was higher in castration‐resistant prostate cancer model cells, promoting cell growth and inhibiting apoptosis (Misawa, Takayama, Urano, & Inoue, ).…”

Section: Discussionmentioning

confidence: 99%

LncRNA Gm2044 promotes 17β‐estradiol synthesis in mpGCs by acting as miR‐138‐5p sponge

Ren

et al. 2019

Molecular Reproduction Devel

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Long noncoding RNAs (lncRNAs) have been demonstrated to play vital roles in mammalian reproduction. Our previous research revealed that lncRNA Gm2044 is highly expressed in mouse spermatocytes and regulates male germ cell function. The gene annotation database BioGPS shows that Gm2044 is not only highly expressed in testicular tissue but also in ovarian tissue, which suggests that Gm2044 may be involved in female reproductive development. In this study, we confirmed that lncRNA Gm2044 promotes 17β‐estradiol synthesis in mouse pre‐antral follicular granulosa cells (mpGCs). Furthermore, bioinformatics methods, western blot, and the luciferase assay proved that Gm2044 functions as a miR‐138‐5p sponge to inhibit the direct target of miR‐138‐5p, Nr5a1, which enhances 17β‐estradiol synthesis through cyp19a1 activation. Taken together, our results provide an insight into the mechanistic roles of lncRNA Gm2044 for 17β‐estradiol synthesis by acting as competing‐endogenous RNAs to modulate the function of mpGCs. Studying the potential lncRNAs, which regulate estradiol release, will be beneficial for the diagnosis and treatment of steroid hormone‐related disease.

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Analysis of the androgen receptor–regulated lncRNA landscape identifies a role for ARLNC1 in prostate cancer progression

Cited by 194 publications

References 73 publications

A positive feedback loop between ZNF205‐AS1 and EGR4 promotes non‐small cell lung cancer growth

A positive feedback loop between ZNF205‐AS1 and EGR4 promotes non‐small cell lung cancer growth

Androgen Receptor Signaling Regulates the Transcriptome of Prostate Cancer Cells by Modulating Global Alternative Splicing

LncRNA Gm2044 promotes 17β‐estradiol synthesis in mpGCs by acting as miR‐138‐5p sponge

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