Chemosensitivity is controlled by p63 modification with ubiquitin-like protein ISG15.
Identification of the cellular mechanisms that mediate cancer cell chemosensitivity is important for developing new cancer treatment strategies. Several chemotherapeutic drugs increase levels of the posttranslational modifier ISG15, which suggests that ISGylation could suppress oncogenesis. However, how ISGylation of specific target proteins controls tumorigenesis is unknown. Here, we identified proteins that are ISGylated in response to chemotherapy. Treatment of a human mammary epithelial cell line with doxorubicin resulted in ISGylation of the p53 family protein p63. An alternative splice variant of p63, ΔNp63α, suppressed the transactivity of other p53 family members, and its expression was abnormally elevated in various human epithelial tumors, suggestive of an oncogenic role for this variant. We showed that ISGylation played an essential role in the downregulation of ΔNp63α. Anticancer drugs, including doxorubicin, induced ΔNp63α ISGylation and caspase-2 activation, leading to cleavage of ISGylated ΔNp63α in the nucleus and subsequent release of its inhibitory domain to the cytoplasm. ISGylation ablated the ability of ΔNp63α to promote anchorage-independent cell growth and tumor formation in vivo as well to suppress the transactivities of proapoptotic p53 family members. These findings establish ISG15 as a tumor suppressor via its conjugation to ΔNp63α and provide a molecular rationale for therapeutic use of doxorubicin against ΔNp63α-mediated cancers.
School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
Young Joo
YJ
Jeon
Mi Gyeong
MG
Jo
Hee Min
HM
Yoo
Se-Hoon
SH
Hong
Jung-Mi
JM
Park
Seung Hyeun
SH
Ka
Kyu Hee
KH
Oh
Jae Hong
JH
Seol
Yong Keun
YK
Jung
Chin Ha
CH
Chung
D020816:Amino Acid Motifs; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D053143:Caspase 2 / Q000378:metabolism; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D002945:Cisplatin / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D016207:Cytokines; D051034:Inhibitor of Apoptosis Proteins; D020033:Protein Isoforms; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins; C074034:ISG15 protein, human; D004317:Doxorubicin; C490360:CASP2 protein, human; D053143:Caspase 2; D003546:Cysteine Endopeptidases; D002945:Cisplatin; D002166:Camptothecin