期刊
MOLECULAR CARCINOGENESIS
卷 -, 期 -, 页码 -出版社
WILEY
DOI: 10.1002/mc.23593
关键词
deubiquitinase; DNA replication stress; RRM2; USP12
RRM2 is a crucial subunit of RNR in cancer cell proliferation. We identified USP12 as the deubiquitinase for RRM2 in NSCLC cells, and found that USP12 depletion caused DNA replication stress and inhibited tumor growth in vivo and in vitro. High expression of USP12 was associated with poor prognosis in NSCLC patients, suggesting it as a potential therapeutic target for NSCLC treatment.
RRM2 is the catalytic subunit of ribonucleotide reductase (RNR), which catalyzes de novo synthesis of deoxyribonucleotide triphosphates (dNTPs) and plays critical roles in cancer cell proliferation. RRM2 protein level is controlled by ubiquitination mediated protein degradation system; however, its deubiquitinase has not been identified yet. Here we showed that ubiquitin-specific peptidase 12 (USP12) directly interacts with and deubiquitinates RRM2 in non-small cell lung cancer (NSCLC) cells. Knockdown of USP12 causes DNA replication stress and retards tumor growth in vivo and in vitro. Meanwhile, USP12 protein levels were positively correlated to RRM2 protein levels in human NSCLC tissues. In addition, high expression of USP12 was associated with poor prognosis in NSCLC patients. Therefore, our study reveals that USP12 is a RRM2 regulator and targeting USP12 could be considered as a potential therapeutical strategy for NSCLC treatment.
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