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The aberrant expression of ADAR1 promotes resistance to BET inhibitors in pancreatic cancer by stabilizing c-Myc.

ABSTRACT: Pancreatic cancer is a malignant tumor with the worst prognosis worldwide. This cancer type requires new insight to help with diagnosis and, eventually, treatment. Adenosine deaminases acting on RNA 1 (ADAR1) is reportedly overexpressed in many types of tumors, such as lung, liver, breast, and esophageal cancers. However, the biological significance and specific mechanism of ADAR1 in pancreatic cancer have not been explored. In this study, we reveal that the expression level of ADAR1 is significantly up-regulated in pancreatic cancer tissues. We also find that highly expressed ADAR1 is closely associated with poor prognosis in pancreatic cancer specimens. Overexpressed ADAR1 equally increased the growth activity of pancreatic cancer cells in vivo and in vitro. We further demonstrate that ADAR1 stabilizes c-Myc through AKT signaling, which contributes to cancer cell resistance to BET inhibitors in pancreatic cancer cells. Moreover, we reveal that EZH2 regulates ADAR1 expression, and EZH2 and BET inhibitors show synergistic inhibition in pancreatic cancer. Collectively, these findings suggest that ADAR1 could serve as a new diagnostic and prognostic marker for the treatment of pancreatic cancer.

SUBMITTER: Sun Y

PROVIDER: S-EPMC7017738 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The aberrant expression of ADAR1 promotes resistance to BET inhibitors in pancreatic cancer by stabilizing c-Myc.

Sun Yan Y Fan Jiquan J Wang Bo B Meng Zibo Z Ren Dianyun D Zhao Jingyuan J Liu Zhiqiang Z Li Dan D Jin Xin X Wu Heshui H

American journal of cancer research 20200101 1

Pancreatic cancer is a malignant tumor with the worst prognosis worldwide. This cancer type requires new insight to help with diagnosis and, eventually, treatment. Adenosine deaminases acting on RNA 1 (ADAR1) is reportedly overexpressed in many types of tumors, such as lung, liver, breast, and esophageal cancers. However, the biological significance and specific mechanism of ADAR1 in pancreatic cancer have not been explored. In this study, we reveal that the expression level of ADAR1 is signific ...[more]

PMID: 32064158

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Project description:BackgroundThe bromodomain and extra-terminal domain (BET) inhibitor is a type of anti-tumor agent, currently being evaluated in phase I and II clinical trials for cancer therapy. It can decrease MYC expression levels and cause effective anti-tumor effects in diverse human cancers. However, its cytotoxic effect and related mechanisms of drug resistance are poorly understood in hepatocellular carcinomas (HCC). Here, we investigated the anti-tumor effects of BET inhibitor on HCC and the molecular mechanisms involved in its associated drug resistance.MethodsWe assessed the cytotoxicity of BET inhibitor on HCC cells compared with sorafenib by cell viability assay, metastasis assay and reproduced the anti-tumor effect in xenograft mouse model. In addition, the molecular mechanisms involved in drug resistance on JQ1-resistant HCC cells were revealed by western blotting, qRT-PCR, whole exome-sequencing and gene-editing technology. Finally, with specific inhibition of EGFR or ERK activity by interference RNAs or inhibitors, the efficacy of the synergistic treatment was investigated using cell viability assay, colony formation, apoptosis and xenograft mouse model.ResultsWe found that JQ1, a commonly used BET bromo-domain inhibitor, offered a better anti-tumor response than sorafenib in MYC-positive HCC cells by inducing apoptosis in vitro and in vivo. Unlike sorafenib, JQ1 treatment significantly impaired mitochondrial respiration and glycolysis in HCC cells. Importantly, we revealed that MAPK activation by a previously undescribed activating mutation of EGFR-I645L, was critical for JQ1 sensitivity through stabilizing oncogenic MYC protein in JQ1-resistant HCC cells. Inhibition of either EGFR or ERK activity overcame the JQ1 resistance and significantly decreased MYC protein level in vitro and in vivo.ConclusionSince MYC amplification is frequently identified in HCC, co-occurring with EGFR amplification, our findings suggest that targeting EGFR signaling might be essential for JQ1 therapy in advanced HCC.

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The aberrant expression of ADAR1 promotes resistance to BET inhibitors in pancreatic cancer by stabilizing c-Myc.

Publications

The aberrant expression of ADAR1 promotes resistance to BET inhibitors in pancreatic cancer by stabilizing c-Myc.

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