Bidirectional regulation of adenosine-to-inosine (A-to-I) RNA editing by DEAH box helicase 9 (DHX9) in cancer

Hong, HuiQi; An, Ömer; Chan, Tim; Ng, Vanessa Hui En; Kwok, Hui Si; Lin, Jaymie Siqi; Liu, Qi; Han, Jian; Tay, Daryl Jin Tai; Tang, Sze Jing; Yang, Henry; Song, Yangyang; Molias, Fernando Bellido; Tenen, Daniel G.; Chen, Leilei

doi:10.1093/nar/gky396

Cited by 45 publications

(54 citation statements)

References 62 publications

(70 reference statements)

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“…We next sought to explore which factors lead to the downregulation of hsa_circ_0004872 in GC. According to previous reports, the formation of circRNA is regulated by RNA binding proteins [ 35 ], such as MBl [ 22 ], QKI [ 36 , 37 ], and ADAR1 [ 38 , 39 ]. We analyzed the public NCBI GEO databases GSE27342 and GSE66229 and found that only ADAR1 expression was significantly higher in GC tissues than in nontumor tissues in both GSE27342 and GSE66229 ( p < 0.0001) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Circular RNA hsa_circ_0004872 inhibits gastric cancer progression via the miR-224/Smad4/ADAR1 successive regulatory circuit

et al. 2020

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Background Emerging evidence has shown that circular RNAs (circRNAs) play a crucial regulatory role in the occurrence and development of cancer. Exploring the roles and mechanisms of circRNAs in tumorigenesis and progression may help to identify new diagnostic markers and therapeutic targets. In the present study, we investigated the role and regulatory mechanism of hsa_circ_0004872 in gastric cancer (GC). Methods qRT-PCR was used to determine the expression of hsa_circ_0004872 in GC tissues and cells. EdU, CCK-8, transwell and scratch wound healing assays were used to assess the role of hsa_circ_0004872 in GC cell proliferation, invasion and migration, respectively. Subcutaneous and tail vein tumor injections in nude mice were used to assess the role of hsa_circ_0004872 in vivo. RIP assay, biotin-coupled probe pull-down assay, FISH and luciferase reporter assay were performed to confirm the relationship between hsa_circ_0004872 and the identified miRNA. ChIP assay, luciferase reporter assay and western blot were used to determine the direct binding of Smad4 to the promoter of the ADAR1 gene. Results In this study, we found that hsa_circ_0004872 was dramatically downregulated in GC tissues compared with adjacent noncancerous tissues. The expression level of hsa_circ_0004872 was associated with tumor size and local lymph node metastasis. Enforced expression of hsa_circ_0004872 inhibited the proliferation, invasion and migration of GC cells, whereas knockdown of hsa_circ_0004872 had the opposite effects. Nude mice experiments showed that ectopic expression of hsa_circ_0004872 dramatically inhibited tumor growth and metastasis in vivo. Moreover, we demonstrated that hsa_circ_0004872 acted as a “molecular sponge” for miR-224 to upregulate the expression of the miR-224 downstream targets p21 and Smad4. Importantly, we found that the RNA-editing enzyme ADAR1 inhibited hsa_circ_0004872 expression and further led to the upregulation of miR-224. Smad4, the downstream target of miR-224, could further affect hsa_circ_0004872 levels by directly binding to the promoter region of ADAR1 to inhibit ADAR1 expression. Conclusions Our findings showed that hsa_circ_0004872 acted as a tumor suppressor in GC by forming a negative regulatory loop consisting of hsa_circ_0004872/miR-224/Smad4/ADAR1. Thus, hsa_circ_0004872 may serve as a potential biomarker and therapeutic target for GC.

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Section: Resultsmentioning

confidence: 99%

Circular RNA hsa_circ_0004872 inhibits gastric cancer progression via the miR-224/Smad4/ADAR1 successive regulatory circuit

et al. 2020

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“…ADARs regulate splicing dependent/independent of editing. We modulated expression of ADAR1/2 in an esophageal squamous carcinoma (ESCC) cell line EC109 that has been used for RNA editing studies previously 33,34 , using lentivirus-mediated silencing and overexpression (Fig. 1a), followed by transcriptomewide RNA-Seq analysis of editing sites and alternative splicing events.…”

Section: Resultsmentioning

confidence: 99%

“…As such, binding of ADAR to exon-intron junction blocks exon recognition by the spliceosome, while binding of ADAR to intra-intronic dsRNA may promote exon inclusion by enhancing intron definition. RNA editing and splicing have been extensively studied, and dysregulation of both processes and their machineries impose considerable impact on cancer development 16,[28][29][30][31][32][33][34][35][36][37][38] . However, there are very limited understanding of the role of their crosstalk in cancer.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we seek to investigate the crosstalk between RNA editing and splicing machineries in the context of cancer, as dysregulations of both machineries are implicated in cancer 14,16,[28][29][30][31][32][33][34][35][36][37][38] . Approximately a hundred high-confidence splicing events regulated by ADAR1 or/and 2 are identified through a comprehensive transcriptome-wide RNA-sequencing (RNA-Seq).…”

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confidence: 99%

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Cis- and trans-regulations of pre-mRNA splicing by RNA editing enzymes influence cancer development

Tang

Shen

et al. 2020

Nat Commun

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RNA editing and splicing are the two major processes that dynamically regulate human transcriptome diversity. Despite growing evidence of crosstalk between RNA editing enzymes (mainly ADAR1) and splicing machineries, detailed mechanistic explanations and their biological importance in diseases, such as cancer are still lacking. Herein, we identify approximately a hundred high-confidence splicing events altered by ADAR1 and/or ADAR2, and ADAR1 or ADAR2 protein can regulate cassette exons in both directions. We unravel a binding tendency of ADARs to dsRNAs that involves GA-rich sequences for editing and splicing regulation. ADAR1 edits an intronic splicing silencer, leading to recruitment of SRSF7 and repression of exon inclusion. We also present a mechanism through which ADAR2 binds to dsRNA formed between GA-rich sequences and polypyrimidine (Py)-tract and precludes access of U2AF65 to 3′ splice site. Furthermore, we find these ADARs-regulated splicing changes per se influence tumorigenesis, not merely byproducts of ADARs editing and binding.

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“…DHX9 has been reported to interact with ADAR1 to regulate A to I editing 19 and protect genome from short interspersed nuclear element (SINE) insertions 1 . Additionally, DHX9 has been reported to unwind nascent double-stranded RNA during co-transcriptional process, and is implicated in the formation of R-loop 8,13 .…”

Section: Discussionmentioning

confidence: 99%

ADAR1 Prevents R-loop Accumulation-Driven ATR Pathway Activation in Ovarian Cancer

Cui¹,

Qian²,

Tian³

et al. 2020

Preprint

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BackgroundAdenosine (A)-to-inosine (I) RNA editing is the most prevalent RNA editing mechanism, in which adenosine deaminases acting on RNA 1 (ADAR1) is a major adenosine deaminase. Increasing evidence suggests that editing dysregulation of ADAR1 plays an important role in human tumorigenesis, while the underlying mechanism remains elusive. MethodsThe clinical relevance of ADAR1 was analyzed by real-time PCR, western blotting and immunohistochemistry of ovarian cancer tissues. ADAR1 function on ovarian cancer cells in vitro were explored by colony formation assay, transwell assay and Brdu-based cell cycle assay in vitro and xenograft models in vivo. Western blotting, immunostaining and DNA/RNA immunoprecipitation-qPCR were conducted to confirm DNA damage and R-loop accumulation in ovarian cancer cells. Co-immunoprecipitation and DNA/RNA immunoprecipitation were performed to detect interaction of DHX9, ADAR1 and R-loop complex in ovarian cancer cells.ResultsWe demonstrated that ADAR1 was highly expressed in ovarian cancer tissues and negatively correlated with progression free survival of ovarian cancer patients. Importantly, silence of ADAR1 repressed ovarian cancer cell growth and colony formation in vitro and inhibited ovarian cancer cell tumorigenesis in vivo. Further cell cycle and transcriptome profile analysis revealed that silence of ADAR1 in ovarian cancer cells induced cell cycle arrest at G1/G0 stage. Mechanically, loss of ADAR1 caused R-loop abnormal accumulation, thereby contributing to single stand DNA break and ATR pathway activation. Additionally, ADAR1 interacted with DHX9 to regulate R-loop complex formation, and A-to-I editing of nascent RNA repressed R-loop formation during co-transcriptional process. ConclusionsOur results identify a novel ADAR1/R-loop/ATR axis critical for ovarian cancer progression and a potential target for ovarian cancer therapy.

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Bidirectional regulation of adenosine-to-inosine (A-to-I) RNA editing by DEAH box helicase 9 (DHX9) in cancer

Cited by 45 publications

References 62 publications

Circular RNA hsa_circ_0004872 inhibits gastric cancer progression via the miR-224/Smad4/ADAR1 successive regulatory circuit

Circular RNA hsa_circ_0004872 inhibits gastric cancer progression via the miR-224/Smad4/ADAR1 successive regulatory circuit

Cis- and trans-regulations of pre-mRNA splicing by RNA editing enzymes influence cancer development

ADAR1 Prevents R-loop Accumulation-Driven ATR Pathway Activation in Ovarian Cancer

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