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

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. ?-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.

SUBMITTER: Shu Y

PROVIDER: S-EPMC7056567 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Shu Yi Y Wang Yi Y Lv Wen-Qiong WQ Peng Dan-Yi DY Li Juan J Zhang Hang H Jiang Guang-Jie GJ Yang Bi-Jie BJ Liu Shan S Zhang Jia J Chen Yan-Hua YH Tang Shi S Wan Ke-Xing KX Yuan Jun-Tao JT Guo Wei W Fu Guo G Qi Xin-Kun XK Liu Zhi-Dai ZD Liu Hai-Yan HY Yang Chao C Zhang Ling-Huan LH Liu Fang-Jie FJ Yu Jie J Zhang Peng-Hui PH Qu Bin B Zhao Hui H He Tong-Chuan TC Zou Lin L

Cancer research 20191210 5

T-cell acute lymphoblastic leukemia (T-ALL) is a type of aggressive leukemia with inferior prognosis. Although activating mutations of <i>NOTCH1</i> 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 stu ...[more]

PMID: 31822496

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Project description:FUSE-binding protein (FBP)-interacting repressor (FIR) is a c-myc transcriptional suppressor. A splice variant of FIR that lacks exon 2 in the transcriptional repressor domain (FIR?exon2) upregulates c-myc transcription by inactivating wild-type FIR. The ratio of FIR?exon2/FIR mRNA was increased in human colorectal cancer and hepatocellular carcinoma tissues. Because FIR?exon2 is considered to be a dominant negative regulator of FIR, FIR heterozygous knockout (FIR?/?) C57BL6 mice were generated. FIR complete knockout (FIR?/?) was embryonic lethal before E9.5; therefore, it is essential for embryogenesis. This strongly suggests that insufficiency of FIR is crucial for carcinogenesis. FIR?/? mice exhibited prominent c-myc mRNA upregulation, particularly in the peripheral blood (PB), without any significant pathogenic phenotype. Furthermore, elevated FIR?exon2/FIR mRNA expression was detected in human leukemia samples and cell lines. Because the single knockout of TP53 generates thymic lymphoma, FIR?/?TP53?/? generated T-cell type acute lymphocytic/lymphoblastic leukemia (T-ALL) with increased organ or bone marrow invasion with poor prognosis. RNA-sequencing analysis of sorted thymic lymphoma cells revealed that the Notch signaling pathway was activated significantly in FIR?/?TP53?/? compared with that in FIR?/?TP53?/? mice. Notch1 mRNA expression in sorted thymic lymphoma cells was confirmed using qRT-PCR. In addition, flow cytometry revealed that c-myc mRNA was negatively correlated with FIR but positively correlated with Notch1 in sorted T-ALL/thymic lymphoma cells. Moreover, the knockdown of TP53 or c-myc using siRNA decreased Notch1 expression in cancer cells. In addition, an adenovirus vector encoding FIR?exon2 cDNA increased bleomycin-induced DNA damage. Taken together, these data suggest that the altered expression of FIR?exon2 increased Notch1 at least partially by activating c-Myc via a TP53-independent pathway. In conclusion, the alternative splicing of FIR, which generates FIR?exon2, may contribute to both colorectal carcinogenesis and leukemogenesis.

Dataset Information

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

Publications

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

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