Abstract：
:MTH1 helps prevent misincorporation of ROS-damaged dNTPs into genomic DNA; however, there is little understanding of how MTH1 itself is regulated. Here, we report that MTH1 is regulated by polyubiquitination mediated by the E3 ligase Skp2. In melanoma cells, MTH1 was upregulated commonly mainly due to its improved stability caused by K63-linked polyubiquitination. Although Skp2 along with other components of the Skp1-Cullin-F-box (SCF) ubiquitin ligase complex was physically associated with MTH1, blocking the SCF function ablated MTH1 ubiquitination and expression. Conversely, overexpressing Skp2-elevated levels of MTH1 associated with an increase in its K63-linked ubiquitination. In melanoma cell lines and patient specimens, we observed a positive correlation of Skp2 and MTH1 expression. Mechanistic investigations showed that Skp2 limited DNA damage and apoptosis triggered by oxidative stress and that MAPK upregulated Skp2 and MTH1 to render cells more resistant to such stress. Collectively, our findings identify Skp2-mediated K63-linked polyubiquitination as a critical regulatory mechanism responsible for MTH1 upregulation in melanoma, with potential implications to target the MAPK/Skp2/MTH1 pathway to improve its treatment. Cancer Res; 77(22); 6226-39. ©2017 AACR.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Wang JY,Liu GZ,Wilmott JS,La T,Feng YC,Yari H,Yan XG,Thorne RF,Scolyer RA,Zhang XD,Jin Ldoi
10.1158/0008-5472.CAN-17-1965subject
Has Abstractpub_date
2017-11-15 00:00:00pages
6226-6239issue
22eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-17-1965journal_volume
77pub_type
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