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Article

Phosphorylation of OCT4 Serine 236 Inhibits Germ Cell Tumor Growth by Inducing Differentiation

1
Research Institute, National Cancer Center, Goyang 10408, Korea
2
Department of Life Science, Ewha Womans University, Seoul 03760, Korea
3
Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang 10408, Korea
4
Department of Pathology, Inje University Ilsan Paik Hospital, Goyang 10308, Korea
5
National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080; Korea
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(9), 2601; https://doi.org/10.3390/cancers12092601
Received: 13 August 2020 / Revised: 9 September 2020 / Accepted: 9 September 2020 / Published: 11 September 2020
(This article belongs to the Section Molecular Cancer Biology)
Octamer-binding transcription factor 4 (OCT4) plays an important role in early embryonic development, but is rarely expressed in adults. However, in many cancer cells, this gene is re-expressed, making the cancer malignant. This present study revealed that inhibiting OCT4 transcriptional activity induces cancer cell differentiation and growth retardation. Specifically, when the phosphorylation of OCT4 serine 236 increases by interfering with the binding of protein phosphatase 1 (PP1) to OCT4, OCT4 loses its transcriptional activity and cancer cells differentiate. Therefore, this study presents the basis for the development of protein-protein interaction inhibitors that inhibit the binding of OCT4 and PP1 for cancer treatment.
Octamer-binding transcription factor 4 (Oct4) plays an important role in maintaining pluripotency in embryonic stem cells and is closely related to the malignancies of various cancers. Although posttranslational modifications of Oct4 have been widely studied, most of these have not yet been fully characterized, especially in cancer. In this study, we investigated the role of phosphorylation of serine 236 of OCT4 [OCT4 (S236)] in human germ cell tumors (GCTs). OCT4 was phosphorylated at S236 in a cell cycle-dependent manner in a patient sample and GCT cell lines. The substitution of endogenous OCT4 by a mimic of phosphorylated OCT4 with a serine-to-aspartate mutation at S236 (S236D) resulted in tumor cell differentiation, growth retardation, and inhibition of tumor sphere formation. GCT cells expressing OCT4 S236D instead of endogenous OCT4 were similar to cells with OCT4 depletion at the mRNA transcript level as well as in the phenotype. OCT4 S236D also induced tumor cell differentiation and growth retardation in mouse xenograft experiments. Inhibition of protein phosphatase 1 by chemicals or short hairpin RNAs increased phosphorylation at OCT4 (S236) and resulted in the differentiation of GCTs. These results reveal the role of OCT4 (S236) phosphorylation in GCTs and suggest a new strategy for suppressing OCT4 in cancer. View Full-Text
Keywords: Oct4; phosphorylation; germ cell tumor; cancer differentiation; OCT4 serine 236; OCT4 inhibitor Oct4; phosphorylation; germ cell tumor; cancer differentiation; OCT4 serine 236; OCT4 inhibitor
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MDPI and ACS Style

Kim, D.K.; Song, B.; Han, S.; Jang, H.; Bae, S.-H.; Kim, H.Y.; Lee, S.-H.; Lee, S.; Kim, J.K.; Kim, H.-S.; Hong, K.-M.; Lee, B.I.; Youn, H.-D.; Kim, S.-Y.; Kang, S.W.; Jang, H. Phosphorylation of OCT4 Serine 236 Inhibits Germ Cell Tumor Growth by Inducing Differentiation. Cancers 2020, 12, 2601. https://doi.org/10.3390/cancers12092601

AMA Style

Kim DK, Song B, Han S, Jang H, Bae S-H, Kim HY, Lee S-H, Lee S, Kim JK, Kim H-S, Hong K-M, Lee BI, Youn H-D, Kim S-Y, Kang SW, Jang H. Phosphorylation of OCT4 Serine 236 Inhibits Germ Cell Tumor Growth by Inducing Differentiation. Cancers. 2020; 12(9):2601. https://doi.org/10.3390/cancers12092601

Chicago/Turabian Style

Kim, Dong K., Bomin Song, Suji Han, Hansol Jang, Seung-Hyun Bae, Hee Y. Kim, Seon-Hyeong Lee, Seungjin Lee, Jong K. Kim, Han-Seong Kim, Kyeong-Man Hong, Byung I. Lee, Hong-Duk Youn, Soo-Youl Kim, Sang W. Kang, and Hyonchol Jang. 2020. "Phosphorylation of OCT4 Serine 236 Inhibits Germ Cell Tumor Growth by Inducing Differentiation" Cancers 12, no. 9: 2601. https://doi.org/10.3390/cancers12092601

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