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A fail-safe system to prevent oncogenesis by senescence is targeted by SV40 small T antigen

Abstract

Whereas large T antigen (LT) of simian virus 40 (SV40) promotes oncogenesis by inactivating the tumor suppressor proteins p53 and pRb, SV40 small T antigen (ST) has been thought to be dispensable for this process. However, here we show that LT promotes both oncogenic growth and senescence in human cells expressing oncogenic Ras and that this latter effect is antagonized by ST. Inactivation of p53 by LT alone promoted the senescence-associated secretory phenotype (SASP), whereas the additional expression of ST attenuated this phenotype, allowing cells to avoid oncogene-induced senescence (OIS) and thereby promoting efficient oncogenesis. ST interacts with and inhibits the function of heterochromatin protein 1–binding protein 3 (HP1BP3), a positive regulator of global microRNA biogenesis, and it thereby triggers aberrant upregulation of B-cell translocation gene 2 (BTG2), which is essential for prevention of SASP and OIS by ST. Collectively, our results indicate that the HP1BP3-BTG2 axis constitutes a fail-safe system to prevent oncogenesis by means of OIS induction, and that this system is hijacked by ST.

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Fig. 1: ST is required for escape from LT-induced transient growth arrest.
Fig. 2: ST suppresses LT-induced excessive production of SASP factors.
Fig. 3: Suppression of SASP factor production by ST is independent of PP2A inhibition.
Fig. 4: ST associates with HP1BP3 and thereby suppresses SASP factor and miRNA production.
Fig. 5: Upregulation of BTG2 contributes to suppression of SASP factor production by ST.
Fig. 6: Depletion of BTG2 increases SASP factor expression in ER cells.
Fig. 7: The HP1BP3-BTG2 axis constitutes a fail-safe system to prevent oncogenesis.

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Acknowledgements

We thank T. Akagi for the pCX4 system as well as hTERT, SV40 ER, and H-RasG12V expression vectors; A. Sakiyama and K. Tsunematsu for technical assistance; members of our laboratories for comments on the manuscript; and A. Ohta for help in preparation of the manuscript. This work was supported in part by KAKENHI grants from Japan Society for the Promotion of Science (JSPS) and the Ministry of Education, Culture, Sports, Science, and Technology of Japan to KIN (18H05215, 17H06301, and 25221303) and to MM (17K19606, 17H05534, and 17H06011) as well as by the Project for Cancer Research and Therapeutic Evolution (P-CREATE) of the Japan Agency for Medical Research and Development (AMED). MM is also supported by Core Research for Evolutionary Science and Technology (CREST, JPMJCR15G4) of the Japan Science and Technology Agency (JST).

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KO designed and performed experiments, analyzed data, and prepared and wrote the manuscript. MM prepared and wrote the manuscript. MK performed flow cytometric analysis. HS performed gene expression profiling interactive analysis. KIN supervised the study and wrote the manuscript.

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Correspondence to Masaki Matsumoto or Keiichi I. Nakayama.

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Oshikawa, K., Matsumoto, M., Kodama, M. et al. A fail-safe system to prevent oncogenesis by senescence is targeted by SV40 small T antigen. Oncogene 39, 2170–2186 (2020). https://doi.org/10.1038/s41388-019-1139-1

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