Chemotherapeutic sensitivity of testicular germ cell tumors under hypoxic conditions is negatively regulated by SENP1-controlled sumoylation of OCT4

Yu Chih Wu, Thai Yen Ling, Shing Hwa Lu, Hung Chih Kuo, Hong Nerng Ho, Shauh Der Yeh, Chia Ning Shen, Yen Hua Huang

研究成果: 雜誌貢獻文章

25 引文 (Scopus)

摘要

Testicular germ cell tumors (TGCT) generally respond well to chemotherapy, but tumors that express low levels of the transcription factor OCT4 are associated with chemoresistance and poor prognosis. Hypoxia is known to induce drug resistance in TGCTs; however, the mechanistic basis for reduced expression of OCT4 and drug resistance is unclear. Here we show that hypoxia reduces OCT4 levels and increases the resistance of embryonal carcinoma (EC) cells to cisplatin and bleomycin. Furthermore, we show that the loss of OCT4 expression under hypoxia can be triggered by sumoylation, which was regulated by SUMO1 and the SUMO1 peptidase SENP1. Under hypoxic conditions, overexpression of SUMO1gg (the active form of SUMO1) not only increased the level of sumoylated OCT4 (Su-OCT4), but also decreased the stability of OCT4 protein. In addition, overexpression of SENP1 reduced the Su-OCT4 level induced by SUMO1gg overexpression, thereby maintaining OCT4 levels and enhancing chemosensitivity. Mechanistic investigations revealed that OCT4 sumoylation occurred at K123, as overexpression of an OCT4-K123R mutant effectively reduced the level of Su-OCT4 under hypoxic conditions. Taken together, our results showed that hypoxia reduces OCT4 expression levels in ECs to increase drug resistance and that these effects could be countered to ablate the suppressive effects of hypoxia on chemosensitivity. Our findings also highlight SENP1 as a potential therapeutic target for drug resistant TGCTs.
原文英語
頁(從 - 到)4963-4973
頁數11
期刊Cancer Research
72
發行號19
DOIs
出版狀態已發佈 - 十月 1 2012

指紋

Sumoylation
Drug Resistance
Embryonal Carcinoma Stem Cells
Protein Stability
Bleomycin
Cisplatin
Peptide Hydrolases
Transcription Factors
Testicular Germ Cell Tumor
Hypoxia
Drug Therapy
Pharmaceutical Preparations
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

引用此文

Chemotherapeutic sensitivity of testicular germ cell tumors under hypoxic conditions is negatively regulated by SENP1-controlled sumoylation of OCT4. / Wu, Yu Chih; Ling, Thai Yen; Lu, Shing Hwa; Kuo, Hung Chih; Ho, Hong Nerng; Yeh, Shauh Der; Shen, Chia Ning; Huang, Yen Hua.

於: Cancer Research, 卷 72, 編號 19, 01.10.2012, p. 4963-4973.

研究成果: 雜誌貢獻文章

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abstract = "Testicular germ cell tumors (TGCT) generally respond well to chemotherapy, but tumors that express low levels of the transcription factor OCT4 are associated with chemoresistance and poor prognosis. Hypoxia is known to induce drug resistance in TGCTs; however, the mechanistic basis for reduced expression of OCT4 and drug resistance is unclear. Here we show that hypoxia reduces OCT4 levels and increases the resistance of embryonal carcinoma (EC) cells to cisplatin and bleomycin. Furthermore, we show that the loss of OCT4 expression under hypoxia can be triggered by sumoylation, which was regulated by SUMO1 and the SUMO1 peptidase SENP1. Under hypoxic conditions, overexpression of SUMO1gg (the active form of SUMO1) not only increased the level of sumoylated OCT4 (Su-OCT4), but also decreased the stability of OCT4 protein. In addition, overexpression of SENP1 reduced the Su-OCT4 level induced by SUMO1gg overexpression, thereby maintaining OCT4 levels and enhancing chemosensitivity. Mechanistic investigations revealed that OCT4 sumoylation occurred at K123, as overexpression of an OCT4-K123R mutant effectively reduced the level of Su-OCT4 under hypoxic conditions. Taken together, our results showed that hypoxia reduces OCT4 expression levels in ECs to increase drug resistance and that these effects could be countered to ablate the suppressive effects of hypoxia on chemosensitivity. Our findings also highlight SENP1 as a potential therapeutic target for drug resistant TGCTs.",
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