ADAR1-mediated regulation of melanoma invasion

Nemlich, Yael; Baruch, Erez N.; Besser, Michal J.; Shoshan, Einav; Bar‐Eli, Menashe; Anafi, Liat; Barshack, Iris; Schachter, Jacob; Ortenberg, Rona; Markel, Gal

doi:10.1038/s41467-018-04600-2

Cited by 40 publications

(33 citation statements)

References 67 publications

(107 reference statements)

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“…In fact, the previous reports have revealed that PAX6 is correlated with angiogenesis, wherein it regulates the differentiation of endothelial cells and is associated with the expression of VEGF [26][27][28]. Our in vitro and in vivo assays suggest that PAX6 is essential for the process of angiogenesis of HUVECs by regulating the process of EMT, which agrees with the previously described consequence of overexpressing PAX6 for the pathogenesis of human cancers [29,30]. In an attempt to rescue the EGFL6-driven abnormal angiogenesis, we found that PAX6 depletion impaired the vascular malformation (Fig.…”

Section: Discussionsupporting

confidence: 92%

See 1 more Smart Citation

Thalidomide targets EGFL6 to inhibit EGFL6/PAX6 axis-driven angiogenesis in small bowel vascular malformation

Tang

Zhang

et al. 2020

Cell. Mol. Life Sci.

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Background Small bowel vascular malformation disease (SBVM) is the most common cause of obscure gastrointestinal bleeding (OGIB). Several studies suggested that EGFL6 was able to promote the growth of tumor endothelial cells by forming tumor vessels. To date, it remains unclear how EGFL6 promotes pathological angiogenesis in SBVM and whether EGFL6 is a target of thalidomide. Methods We took advantage of SBVM plasma and tissue samples and compared the expression of EGFL6 between SBVM patients and healthy people via ELISA and Immunohistochemistry. We elucidated the underlying function of EGFL6 in SBVM in vitro and by generating a zebrafish model that overexpresses EGFL6, The cycloheximide (CHX)-chase experiment and CoIP assays were conducted to demonstrate that thalidomide can promote the degradation of EGFL6 by targeting CRBN. Results The analysis of SBVM plasma and tissue samples revealed that EGFL6 was overexpressed in the patients compared to healthy people. Using in vitro and in vivo assays, we demonstrated that an EMT pathway triggered by the EGFL6/PAX6 axis is involved in the pathogenesis of SBVM. Furthermore, through in vitro and in vivo assays, we elucidated that thalidomide can function as anti-angiogenesis medicine through the regulation of EGFL6 in a proteasome-dependent manner. Finally, we found that CRBN can mediate the effect of thalidomide on EGFL6 expression and that the CRBN protein interacts with EGFL6 via a Lon N-terminal peptide. Conclusion Our findings revealed a key role for EGFL6 in SBVM pathogenesis and provided a mechanism explaining why thalidomide can cure small bowel bleeding resulting from SBVM.

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Section: Discussionsupporting

confidence: 92%

“…6f). To date, although there has been no direct evidence to demonstrate that EGFL6 is correlated with PAX6, a study has shown that PAX6 regulates ITGB3 expression as a transcription factor [30]. Moreover, the members of the integrin family are Fig.…”

Section: Discussionmentioning

confidence: 99%

Thalidomide targets EGFL6 to inhibit EGFL6/PAX6 axis-driven angiogenesis in small bowel vascular malformation

Tang

Zhang

et al. 2020

Cell. Mol. Life Sci.

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“…Different possible mechanisms mediated by ADAR1 have also been revealed to play a role in carcinogenesis. In some of the studies, ADAR1 were found to regulate specific targets at the transcriptional- and post-transcriptional level and thereby inhibit cancer progression [31,64]. Tumor cells, particularly melanoma cells, has been demonstrated in these studies to downregulate ADAR1 expression in order to survive and migrate.…”

Section: The Role Of Adar1 In Modulating Specific Editing Substratmentioning

confidence: 99%

ADAR1 Editing and its Role in Cancer

Öhman

2018

Genes

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It is well established that somatic mutations and escape of immune disruption are two essential factors in cancer initiation and progression. With an increasing number of second-generation sequencing data, transcriptomic modifications, so called RNA mutations, are emerging as significant forces that drive the transition from normal cell to malignant tumor, as well as providing tumor diversity to escape an immune attack. Editing of adenosine to inosine (A-to-I) in double-stranded RNA, catalyzed by adenosine deaminases acting on RNA (ADARs), is one dynamic modification that in a combinatorial manner can give rise to a very diverse transcriptome. Since the cell interprets inosine as guanosine (G), A-to-I editing can result in non-synonymous codon changes in transcripts as well as yield alternative splicing, but also affect targeting and disrupt maturation of microRNAs. ADAR-mediated RNA editing is essential for survival in mammals, however, its dysregulation causes aberrant editing of its targets that may lead to cancer. ADAR1 is commonly overexpressed, for instance in breast, lung, liver and esophageal cancer as well as in chronic myelogenous leukemia, where it promotes cancer progression. It is well known that ADAR1 regulates type I interferon (IFN) and its induced gene signature, which are known to operate as a significant barrier to tumor formation and progression. Adding to the complexity, ADAR1 expression is also regulated by IFN. In this review, we discussed the regulatory mechanisms of ADAR1 during tumorigenesis through aberrant editing of specific substrates. Additionally, we hypothesized that elevated ADAR1 levels play a role in suppressing an innate immunity response in cancer cells.

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“…These editing events have been shown to play a role in self versus non-self RNA recognition in the innate immune response, and thus dysregulation of ADAR1 leads to immune-related diseases such as Aicardi-Goutieres syndrome (AGS) (Blango and Bass, 2016; Liddicoat et al, 2015; Mannion et al, 2014; Pestal et al, 2015; Rice et al, 2012). ADAR1 levels also correlate with tumor aggressiveness, as increases in ADAR1 editing suppress the innate immune response in tumors; accordingly, ADAR1 ablation helps with cancer therapy (Bhate et al, 2019; Gannon et al, 2018; Ishizuka et al, 2019; Liu et al, 2019; Nemlich et al, 2018). While the majority of ADAR1-regulated editing sites are found in repeat regions, ADAR2 is primarily responsible for editing adenosines found in non-repeat regions, particularly in the brain (Tan et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

Freund

Sapiro

et al. 2019

Preprint

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13Adenosine-to-Inosine RNA editing is catalyzed by ADAR enzymes that deaminate adenosine to 14 inosine. While many RNA editing sites are known, few trans regulators have been identified. We 15 perform BioID followed by mass-spectrometry to identify trans regulators of ADAR1 and ADAR2 16 in HeLa and M17 neuroblastoma cells. We identify known and novel ADAR-interacting proteins. 17Using ENCODE data we validate and characterize a subset of the novel interactors as global or 18 site-specific RNA editing regulators. Our set of novel trans regulators includes all four members 19 of the DZF-domain-containing family of proteins: ILF3, ILF2, STRBP, and ZFR. We show that 20 these proteins interact with each ADAR and modulate RNA editing levels. We find ILF3 is a 21 global negative regulator of editing. This work demonstrates the broad roles RNA binding 22 proteins play in regulating editing levels and establishes DZF-domain containing proteins as a 23 group of highly influential RNA editing regulators. 24 25 47 the majority of ADAR1-regulated editing sites are found in repeat regions, ADAR2 is primarily 48 responsible for editing adenosines found in non-repeat regions, particularly in the brain (Tan et 49 al., 2017). ADAR2-regulated sites in non-repetitive regions include a number of editing events 50 that alter the protein-coding sequences of neuronal RNAs, including GluR2, which encodes a 51 glutamate receptor in which RNA editing is necessary for its proper function. Further 52 demonstrating its important role in neuronal editing, dysregulation of human ADAR2 is 53 associated with multiple neurological diseases, including amyotrophic lateral sclerosis, 54 astrocytoma and transient forebrain ischemia (Slotkin and Nishikura, 2013; Tran et al., 2019). 55Maintaining RNA editing levels is critical for human health, but how RNA editing levels are 56 regulated at specific editing sites across tissues and development is poorly understood. 58While RNA sequence and structure are critical determinants of editing levels, studies querying 59 tissue-specific and developmental-stage-specific editing levels show that the level of editing at 60 the same editing site can vary greatly between individuals and tissues. These changes do not 61 always correlate with ADAR mRNA or protein expression, suggesting a complex regulation of 62 editing events by factors other than ADAR proteins (Sapiro et al., 2019; Tan et al., 2017; 63 Wahlstedt et al., 2009). Recently, an analysis of proteins with an RNA-binding domain profiled 64 by ENCODE suggested that RNA-binding proteins play a role in RNA editing regulation. Further, 65 in mammals, a small number of trans regulators of editing have been identified through 66 functional experiments (Quinones-Valdez et al., 2019). Some of these trans regulators of editing 67 are site-specific, in that they affect editing levels at only a small subset of editing sites. These 68 include RNA binding proteins such as DHX15, HNRNPA2/B1, RPS14, TDP-43, Drosha and 69 Ro60 (Garncarz et al., 2013; Quinones-Valdez ...

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ADAR1-mediated regulation of melanoma invasion

Cited by 40 publications

References 67 publications

Thalidomide targets EGFL6 to inhibit EGFL6/PAX6 axis-driven angiogenesis in small bowel vascular malformation

Thalidomide targets EGFL6 to inhibit EGFL6/PAX6 axis-driven angiogenesis in small bowel vascular malformation

ADAR1 Editing and its Role in Cancer

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

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