Repair shielding of platinum-DNA lesions in testicular germ cell tumors by high-mobility group box protein 4 imparts cisplatin hypersensitivity

Cisplatin is the most commonly used anticancer drug for the treatment of testicular germ cell tumors (TGCTs). The hypersensitivity of TGCTs to cisplatin is a subject of widespread interest. Here, we show that high-mobility group box protein 4 (HMGB4), a protein preferentially expressed in testes, un...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 5; pp. 950 - 955
Main Authors: Awuah, Samuel G, Riddell, Imogen A, Lippard, Stephen J
Format: Journal Article
Language:English
Published: United States 31.01.2017
Subjects:
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Cisplatin - pharmacology
CRISPR-Cas Systems
DNA Damage
DNA Repair
Gene Editing
HMGB Proteins - genetics
HMGB Proteins - metabolism
Humans
Neoplasms, Germ Cell and Embryonal - metabolism
Testicular Neoplasms - metabolism
testicular cancer
high-mobility group protein
platinum anticancer drug
ISSN:1091-6490
Online Access:Get more information
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Summary:Cisplatin is the most commonly used anticancer drug for the treatment of testicular germ cell tumors (TGCTs). The hypersensitivity of TGCTs to cisplatin is a subject of widespread interest. Here, we show that high-mobility group box protein 4 (HMGB4), a protein preferentially expressed in testes, uniquely blocks excision repair of cisplatin-DNA adducts, 1,2-intrastrand cross-links, to potentiate the sensitivity of TGCTs to cisplatin therapy. We used CRISPR/Cas9-mediated gene editing to knockout the HMGB4 gene in a testicular human embryonic carcinoma and examined cellular responses. We find that loss of HMGB4 elicits resistance to cisplatin as evidenced by cell proliferation and apoptosis assays. We demonstrate that HMGB4 specifically inhibits repair of the major cisplatin-DNA adducts in TGCT cells by using the human TGCT excision repair system. Our findings also reveal characteristic HMGB4-dependent differences in cell cycle progression following cisplatin treatment. Collectively, these data provide convincing evidence that HMGB4 plays a major role in sensitizing TGCTs to cisplatin, consistent with shielding of platinum-DNA adducts from excision repair.
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ISSN:1091-6490
DOI:10.1073/pnas.1615327114