Abstract
Abstract Well-differentiated testicular germ cell tumors (TGCTs) are more drug insensitive and have a poorer prognosis than pluripotent germ cell tumors. However, the mechanism underlying the differentiation regulation of pluripotent seminomas/embryonal carcinomas (ECs) still remains largely unknown. Herein, we demonstrated an important role of SUMO1/sentrin specific peptidase 1 (SENP1) in the sumoylation and stability of the OCT4 protein in the drug sensitivity of hypoxic ECs. Hypoxia decreased the OCT4 protein level, but not the messenger RNA level, in pluripotent ECs. Hypoxic challenge and SUMO1 overexpression increased OCT4 sumoylation and protein instability. A further mutation at the specific OCT4 lysine 123 (HA-OCT4-K123R) effectively suppressed OCT4 sumoylation and protein instability, demonstrating the important role of the specific sumoylation of lysine 123 in OCT4 protein stability under hypoxia. Consistently, overexpression of SUMO1 decreased the endogenous OCT4 half-life in hypoxic NCCIT cells. The band-shift of endogenous sumoylated OCT4 in hypoxic NCCIT cells was demonstrated using Western blot analysis. SENP1 effectively suppressed OCT4 sumoylation and increased OCT4 stability and drug sensitivity in hypoxic NCCIT cells in vitro. Furthermore, overexpression of SENP1 in hypoxic NCCIT cells increased the drug sensitivity in a nude mice model, demonstrating the upstream regulation of SENP1 in OCT4 sumoylation, protein stability, and the drug susceptibility of NCCIT cells. In summary, we demonstrated that the sumoylation regulator, SENP1, positively regulates OCT4 stability and drug sensitivity of pluripotent EC cells through sumoylation. Findings of this study provide insights into the regulation by sumoylation of pluripotent TGCTs differentiation, which has the potential for pharmacological development of effective therapeutic targeting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 423. doi:1538-7445.AM2012-423
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