Journal
BIOCHEMICAL JOURNAL
Volume 479, Issue 19, Pages 2063-2086Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BCJ20220102
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Funding
- Cancer Research UK [C1443/A22095, C1443/A12750, C309/A11566]
- Leukemia Lymphoma Research [11022]
- Cancer Research UK
- Wellcome Trust [094409]
- University of Kent
- Biotechnology and Biosciences Research Council (BBSRC) [BB/M012557/1, BB/R000182/1]
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The study found that deleting c-Rel results in earlier onset of lymphoma, contrary to the expected function of this NF-xB subunit. E mu-Myc/cRel-/- lymphomas were shown to have a major defect in the CHK1 pathway, involving a loss of CHK1 protein expression and resistance to CHK1 inhibitor treatment.
Previously, we discovered that deletion of c-Rel in the E mu-Myc mouse model of lymph-oma results in earlier onset of disease, a finding that contrasted with the expected func-tion of this NF-xB subunit in B-cell malignancies. Here we report that E mu-Myc/cRel-/- cells have an unexpected and major defect in the CHK1 pathway. Total and phospho proteomic analysis revealed that E mu-Myc/cRel-/- lymphomas highly resemble wild-type (WT) E mu-Myc lymphomas treated with an acute dose of the CHK1 inhibitor (CHK1i) CCT244747. Further analysis demonstrated that this is a consequence of E mu-Myc/cRel-/ - lymphomas having lost expression of CHK1 protein itself, an effect that also results in resistance to CCT244747 treatment in vivo. Similar down-regulation of CHK1 protein levels was also seen in CHK1i resistant U2OS osteosarcoma and Huh7 hepatocellular carcinoma cells. Further investigation revealed that the deubiquitinase USP1 regulates CHK1 proteolytic degradation and that its down-regulation in our model systems is responsible, at least in part, for these effects. We demonstrate that treating WT E mu-Myc lymphoma cells with the USP1 inhibitor ML323 was highly effective at reducing tumour burden in vivo. Targeting USP1 activity may thus be an alternative therapeutic strategy in MYC-driven tumours.
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