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

Cancer Res. 2020 Mar 1;80(5):988-998. doi: 10.1158/0008-5472.CAN-19-1471. Epub 2019 Dec 10.

Abstract

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. β-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 β-arrestin1 in T-ALL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Adolescent
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Child
  • Child, Preschool
  • Female
  • Gene Expression Regulation, Leukemic
  • Humans
  • Male
  • Mice
  • MicroRNAs / metabolism*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Proteolysis
  • RNA-Seq
  • Receptor, Notch1 / metabolism*
  • Signal Transduction / genetics
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Xenograft Model Antitumor Assays
  • beta-Arrestin 1 / genetics*
  • beta-Arrestin 1 / metabolism

Substances

  • 3' Untranslated Regions
  • ARRB1 protein, human
  • MIRN223 microRNA, human
  • MicroRNAs
  • NOTCH1 protein, human
  • Receptor, Notch1
  • Tumor Suppressor Proteins
  • beta-Arrestin 1