Abstract
Resistance to platinum-based chemotherapy is one of the most important reasons for treatment failure in advanced non-small cell lung cancer, but the underlying mechanism is extremely complex and unclear. The present study aimed to investigate the correlation of ubiquitin-specific peptidase 22 (USP22) with acquired resistance to cisplatin in lung adenocarcinoma. In this study, we found that overexpression of USP22 could lead to cisplatin resistance in A549 cells. USP22 and its downstream proteins γH2AX and Sirt1 levels are upregulated in the cisplatin- resistant A549/CDDP cell line. USP22 enhances DNA damage repair and induce cisplatin resistance by promoting the phosphorylation of histone H2AX via deubiquitinating histone H2A. In addition, USP22 decreases the acetylation of Ku70 by stabilizing Sirt1, thus inhibiting Bax-mediated apoptosis and inducing cisplatin resistance. The cisplatin sensitivity in cisplatin-resistant A549/CDDP cells was restored by USP22 inhibition in vivo and vitro. In summary, our findings reveal the dual mechanism of USP22 involvement in cisplatin resistance that USP22 can regulate γH2AX-mediated DNA damage repair and Ku70/Bax-mediated apoptosis. USP22 is a potential target in cisplatin-resistant lung adenocarcinoma and should be considered in future therapeutic practice.
Highlights
Non-small cell lung cancer (NSCLC), which comprises 80 to 85% of all lung cancers, is the most fatal cancer worldwide, with a 5-year survival as low as 13% (Molina et al, 2008; Siegel et al, 2015)
The cholecystokinin 8 (CCK8) results showed that the IC50 of 24h and 48h cisplatin treatment was 1.26 ± 0.05 μM and 0.63 ± 0.04 μM for A549USP22 (A549 cells overexpressing ubiquitin-specific peptidase 22 (USP22)), which was 2.6 and 3.0-fold higher compared with the A549 cell line (Figure 1B), respectively
The results showed that the number of colonies formed by A549-USP22 was 5.2-fold higher compared with the control cells (Figure 1C)
Summary
Non-small cell lung cancer (NSCLC), which comprises 80 to 85% of all lung cancers, is the most fatal cancer worldwide, with a 5-year survival as low as 13% (Molina et al, 2008; Siegel et al, 2015). Platinum-based doublet chemotherapy regimens are the most standard first-line treatment strategy for advanced NSCLC, especially in patients without driver gene mutations (Zappa and Mousa, 2016). The efficacy of standard firstline chemotherapy is only approximately 30%, and resistance to platinum-based chemotherapy including cisplatin is one of the most important reasons for treatment failure and poor prognosis in NSCLC (Fennell et al, 2016). It is well known that cisplatin acts on multiple cellular targets representing diverse signal transduction pathways (Rose et al, 2014). The mechanism underlying cisplatin resistance is extremely complex and multi-factorial. Further elucidation of molecular mechanisms underlying cisplatin resistance would improve the efficacy and prognosis of NSCLC
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