Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive leukemia that is primarily caused by aberrant activation of the NOTCH1 signaling pathway. Recent studies have revealed that posttranslational modifications, such as ubiquitination, regulate NOTCH1 stability, activity, and localization. However, the specific deubiquitinase that affects NOTCH1 protein stability remains unestablished. Here, we report that ubiquitin-specific protease 7 (USP7) can stabilize NOTCH1. USP7 deubiquitinated NOTCH1 in vivo and in vitro, whereas knockdown of USP7 increased the ubiquitination of NOTCH1. USP7 interacted with NOTCH1 protein in T-ALL cells, and the MATH and UBL domains of USP7 were responsible for this interaction. Depletion of USP7 significantly suppressed the proliferation of T-ALL cells in vitro and in vivo, accompanied by downregulation of the NOTCH1 protein level. Similarly, pharmacologic inhibition of USP7 led to apoptosis of T-ALL cells. More importantly, we found that USP7 was significantly upregulated in human T-ALL cell lines and patient samples, and a USP7 inhibitor exhibited cell cytotoxicity toward primary T-ALL cells, indicating the clinical relevance of these findings. Overall, our results demonstrate that USP7 is a novel deubiquitinase that stabilizes NOTCH1. Therefore, USP7 may be a promising therapeutic target in the currently incurable T-ALL.
Highlights
The NOTCH1 receptor is a transmembrane protein that serves as a ligand-activated transcription factor that regulates a great diversity of cellular events, including cell proliferation, survival, metastasis, and differentiation.[1]
ubiquitin-specific protease 7 (USP7) interacts with intracellular domain of NOTCH1 (ICN1) we explored whether USP7 interacts with ICN1 using an immunoprecipitation assay and found that ectopically expressed Myc-ICN1 interacted with FLAG-USP7 (Fig. 2a)
Knockdown of USP7 reduces ICN1 protein levels and suppresses TALL cell proliferation in vitro and in vivo Since NOTCH1 plays a significant role in T-cell acute lymphoblastic leukemia (T-ALL) pathogenesis, we proposed that loss of function of USP7, which deubiquitinates and stabilizes ICN1, might inhibit T-ALL cell growth
Summary
The NOTCH1 receptor is a transmembrane protein that serves as a ligand-activated transcription factor that regulates a great diversity of cellular events, including cell proliferation, survival, metastasis, and differentiation.[1]. It is known that the ubiquitin-proteasome system and lysosome pathway participate in the regulation of NOTCH1 turnover. More than the half of DUBs belong to the ubiquitin-specific protease (USP) subfamily.[17] To date, eIF3f has been reported to function as a deubiquitinase and to regulate the activation of NOTCH1.18 the deubiquitinase that modulates the stability of NOTCH1 protein remains unknown. USP7 changes the localization of monoubiquitinated FOXO4 and PTEN through removal of the single ubiquitin molecule[20,21,22] and can regulate the stability of p53, MDM2, N-MYC, TRIP12, FOXP3, ASXL1, UHRF1, PHF8, and DNMT1.23–30 Many of the preceding factors are critical in cancer development, epigenetic control, cell signaling, DNA damage repair, and immune responses.
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