USP7 and Daxx regulate mitosis progression and taxane sensitivity by affecting stability of Aurora-A kinase

Abstract

A large number of patients are resistant to taxane-based chemotherapy. Functional mitotic checkpoints are essential for taxane sensitivity. Thus, mitotic regulators are potential markers for therapy response and could be targeted for anticancer therapy. In this study, we identified a novel function of ubiquitin (Ub)-specific processing protease-7 (USP7) that interacts and cooperates with protein death domain-associated protein (Daxx) in the regulation of mitosis and taxane resistance. Depletion of USP7 impairs mitotic progression, stabilizes cyclin B and reduces stability of the mitotic E3 Ub ligase, checkpoint with forkhead and Ring-finger (CHFR). Consequently, cells with depleted USP7 accumulate Aurora-A kinase, a CHFR substrate, thus elevating multipolar mitoses. We further show that these effects are independent of the USP7 substrate p53. Thus, USP7 and Daxx are necessary to regulate proper execution of mitosis, partially via regulation of CHFR and Aurora-A kinase stability. Results from colony formation assay, in silico analysis across the NCI60 platform and in breast cancer patients suggest that USP7 levels inversely correlate with response to taxanes, pointing at the USP7 protein as a potential predictive factor for taxane response in cancer patients. In addition, we demonstrated that inhibition of Aurora-A attenuates USP7-mediated taxane resistance, suggesting that combinatorial drug regimens of Taxol and Aurora-A inhibitors may improve the outcome of chemotherapy response in cancer patients resistant to taxane treatment. Finally, our study offers novel insights on USP7 inhibition as cancer therapy.

Ubiquitin‐specific protease 7 accelerates p14ARF degradation by deubiquitinating thyroid hormone receptor‐interacting protein 12 and promotes hepatocellular carcinoma progression

“…Recently, RNA interference (RNAi) was used to systematically screen cancer‐related USPs in the human genome . In this model, USP7 silencing exerted selective antiproliferative effects by inducing cell‐cycle arrest, although only in cancer cells retaining wild‐type (WT) p53 . Consistent with these reports, USP7 silencing increases steady‐state p53 levels by promoting murine double minute 2 homolog (Mdm2) degradation .…”

Usp7 protects genomic stability by regulating Bub3

“…In our experiments we observed that mitotic timing was considerably longer by cyclin B stability or time lapse microscopy in USP7 depleted cells ([46], Fig. 5C and D) and in cells exposed to USP7 inhibitors (Fig.…”

Using CellMiner 1.6 for Systems Pharmacology and Genomic Analysis of the NCI-60

“…CellMiner previously has enabled us to: i) identify promoter-proximal transcriptional pausing in human genes (37, 38), ii) discover the helicase SLFN11 as a causal determinant of response to DNA-damaging agents (18), iii) recognize the regulation of MYC expression by miR-375 (39), iv) recognize the importance of MYC as a driver of mitochondrial genes (40), v) reveal genetic inactivation or endogenous activation of CHEK2 across the NCI-60 (40); vi) link USP7 and Daxx to taxane resistance (41), vi) link TP53 wild type status, Mdm2 transcript level, and miR-34a transcript level with nutlin activity (10), viii) reveal the interrelationship between RAS (H, K, and NRAS)-BRAF-PTEN mutational status, EGFR expression, and ERBB2 expression with erlotinib activity (10), ix) demonstrate the strong correlation between ABCB1 expression and doxorubicin activity (2), x) recognize both known and novel genes expression levels, microRNA expression levels, and drug activities with a colon-specific pattern input to “Pattern comparison” (2), xi) identify predominant co-regulation among cell migration genes (42), xii) identify co-regulation among kinetochore genes, their prospective regulatory elements, and their association with genomic instability (43), xiii) show the connection between accumulation of mass homozygotes in the cancer cell lines as compared to non-cancerous HapMap trios (44), xiv) identify the drug Ro5-3335 as a candidate treatment for core binding factor leukemias (45), xv) associate CDKN2A DNA copy number and expression to mitoxantrone activity (8), xvi) define an epithelial gene expression signature (46), and xvii) recognize the composite relationship between the mutational status of multiple genes from the EGFR-ERBB2 pathway and drug response, including the directionality of that influence as a function of molecular pathway considerations (14). The diversity among these observations gives an indication of the boundless scope and range of the types of possible discoveries that can be made using the NCI-60 database and CellMiner set of tools.…”