The role of USP51 in attenuating chemosensitivity of lung cancer cells to cisplatin by regulating DNA damage response.

ABSTRACT

Lung cancer is the most frequent type of cancer affecting both men and women globally, and it is associated with a high mortality rate. It is clinically treated with cisplatin, a platinum-based drug that works by generating DNA lesions, which activates DNA damage response and induces cell death. However, chemoresistance by cancer cells limits the clinical usefulness of cisplatin as an anticancer drug. Here, we uncovered a role of ubiquitin-specific protease 51 (USP51) in the chemosensitivity of lung cancer cells to cisplatin by regulating DNA damage response. USP51 was more upregulated in lung cancer tissues of chemotherapy-resistant patients than those of chemotherapy-sensitive patients with adjacent, nontumor tissues. USP51 overexpression in lung cancer cells in vitro reduced γ-H2AX formation and promoted checkpoint kinase 1 (CHK1) phosphorylation, whereas USP51 knockdown showed opposite effects, indicating that USP51 played an important role in promoting DNA damage repair. Finally, USP51 knockdown weakened cisplatin resistance in A549/DDP cells and significantly suppressed tumor growth in vivo, suggesting that a USP51 inhibitor combined with cisplatin may be considered as an effective treatment strategy to eliminate drug-resistant lung cancer cells.