Dataset Information

Circular RNA Expression is Suppressed by Androgen Receptor (AR) Regulated Adenosine DeAminase that act on RNA (ADAR1) in Human Hepatocellular Carcinoma

ABSTRACT: Hepatocellular carcinoma (HCC) is a heterogeneous malignancy as a result of complex genetic and epigenetic alterations. HCC is characterized by a clear gender disparity for which lacking a clear mechanistic understanding. By utilizing circular RNA (circRNA) microarray survey coupled with in vitro analysis, we analyzed the influence of androgen receptor (AR) on circRNA expression in HCC. Our results indicated that AR could suppress circRNA expression by up-regulating adenosine deaminase that act on RNA (ADAR1) p110 at a transcriptional level. Reporter assay further confirmed the role of AR as a transcriptional activator of ADAR1 expression. Furthermore, data collected from our center strongly suggest that ADAR1 expression can effectively predict HCC patients’ prognosis and an abnormal overexpression of ADAR1 is positively correlated with AR in HCC. In addition, we found CircARSP91 (hsa_circ_0085154), one of the circRNAs down-regulated by AR in an ADAR1-dependent manner, could inhibit HCC tumor growth both in vitro and in vivo. These findings highlight the fact that AR as a contributing factor for gender disparity in HCC can cause complex consequences though regulation of circRNA expression. Better understanding of roles of circRNA during HCC initiation and progression will be a key to develop novel HCC therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94520 | GEO | 2020/02/01

REPOSITORIES: GEO

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Project description:Sensing of double-stranded RNA (dsRNA) is an important component of innate immunity. Proteins like PKR and MDA5 recognize dsRNA and activate various pathways to fight viral infection. In addition to viral dsRNA, many endogenous RNAs containing double-stranded regions can be misrecognized as immunogenic. The RNA editing enzyme ADAR1, specifically its p150 isoform, has been shown to suppress activation of PKR and MDA5 through its A-to-I editing activity. While the cytoplasmic ADAR1-p150 isoform has been well established within this role, the functions of the nuclear ADAR1-p110 isoform are less understood. To address this knowledge gap, we utilized proximity labeling by APEX2 to identify putative ADAR1-p110 interacting proteins. We identified 110 proteins across three breast cancer cell lines that either interact with p110 or are within close proximity. Many of these proteins have known roles in RNA metabolism. Nine of the identified proteins belong to the DEAD or DEAH box families of RNA helicases, including DHX9. DHX9 is overexpressed in breast cancer, with expression closely correlated with that of p110. By co-immunoprecipitation we confirmed that p110 interacts with DHX9. Knockdown of DHX9 in several triple-negative breast cancer cell lines caused cell death and activation of the dsRNA sensor PKR. In two cell lines that are refractory to knockdown of ADAR1, the combined knockdown of DHX9 and ADAR1 caused a substantial increase in PKR activity, where knockdown of either alone had no effect. Knockdown of DHX9 and ADAR1 caused activation of the type I IFN pathway, RNase L and NF-KB signaling. Activation of these proteins and pathways was not seen with individual knockdown of ADAR1 or DHX9. Activation of PKR following combined knockdown of ADAR1 and DHX9 could be rescued by expression of p110, p150, DHX9, and catalytically inactive DHX9. Additionally PKR activation could be rescued by the dsRBM of DHX9, revealing an important role for dsRBMs in suppressing PKR activation. Together these results reveal an important role for DHX9 in suppressing dsRNA sensing by multiple pathways.

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Dataset Information

Circular RNA Expression is Suppressed by Androgen Receptor (AR) Regulated Adenosine DeAminase that act on RNA (ADAR1) in Human Hepatocellular Carcinoma

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