ARRB1-Promoted NOTCH1 Degradation Is Suppressed by OncomiR miR-223 in T-cell Acute Lymphoblastic Leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is a type of aggressive leukemia with inferior prognosis. Although activating mutations of NOTCH1 are observed in most T-ALL cases, these mutations alone are not sufficient to drive the full development of T-ALL. ?-Arrestins (ARRB) are versatile and multifunctional adapter proteins that regulate diverse cellular ...
functions, including promoting the development of cancer. However, the role of ARRBs in T-ALL has largely remained elusive. In this study, we showed that ARRB1 is expressed at low levels in assayed T-ALL clinical samples and cell lines. Exogenous ARRB1 expression inhibited T-ALL proliferation and improved the survival of T-ALL xenograft animals. ARRB1 facilitated NOTCH1 ubiquitination and degradation through interactions with NOTCH1 and DTX1. Mechanistically, the oncogenic miRNA (oncomiR) miR-223 targets the 3'-UTR of ARRB1 (BUTR) and inhibits its expression in T-ALL. Furthermore, overexpression of the ARRB1-derived miR-223 sponge suppressed T-ALL cell proliferation and induced apoptosis. Collectively, these results demonstrate that ARRB1 acts as a tumor suppressor in T-ALL by promoting NOTCH1 degradation, which is inhibited by elevated miR-223, suggesting that ARRB1 may serve as a valid drug target in the development of novel T-ALL therapeutics.Significance: These findings highlight a novel tumor suppressive function of the adaptor protein ?-arrestin1 in T-ALL.
Mesh Terms:
3' Untranslated Regions, Adolescent, Animals, Cell Line, Tumor, Cell Proliferation, Child, Child, Preschool, Female, Gene Expression Regulation, Leukemic, Humans, Male, Mice, MicroRNAs, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Proteolysis, RNA-Seq, Receptor, Notch1, Signal Transduction, Tumor Suppressor Proteins, Xenograft Model Antitumor Assays, beta-Arrestin 1
Cancer Res
Date: Dec. 01, 2019
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