The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA

Andrea Rabellino, Brandon Carter, Georgia Konstantinidou, Shwu Yuan Wu, Alessandro Rimessi, Lauren A. Byers, John V. Heymach, Luc Girard, Cheng Ming Chiang, Julie Teruya-Feldstein, Pier Paolo Scaglioni

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Abstract

The ubiquitin-like SUMO proteins covalently modify protein substrates and regulate their functional properties. In a broad spectrum of cancers, the tumor suppressor PML undergoes ubiquitin-mediated degradation primed by CK2 phosphorylation. Here, we report that the SUMO E3-ligase inhibitor PIAS1 regulates oncogenic signaling through its ability to sumoylate PML and the PML-RARA oncoprotein of acute promyelocytic leukemia (APL). PIAS1-mediated SUMOylation of PML promoted CK2 interaction and ubiquitin/proteasomemediated degradation of PML, attenuating its tumor suppressor functions. In addition, PIAS1-mediated SUMOylation of PML-RARA was essential for induction of its degradation by arsenic trioxide, an effective APL treatment. Moreover, PIAS1 suppression abrogated the ability of arsenic trioxide to trigger apoptosis in APL cells. Lastly, PIAS1 was also essential for PML degradation in non-small cell lung carcinoma (NSCLC) cells, and PML and PIAS1 were inversely correlated in NSCLC cell lines and primary specimens. Together, our findings reveal novel roles for PIAS1 and the SUMOylation machinery in regulating oncogenic networks and the response to leukemia therapy.

Original languageEnglish (US)
Pages (from-to)2275-2284
Number of pages10
JournalCancer research
Volume72
Issue number9
DOIs
StatePublished - May 1 2012

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Rabellino, A., Carter, B., Konstantinidou, G., Wu, S. Y., Rimessi, A., Byers, L. A., Heymach, J. V., Girard, L., Chiang, C. M., Teruya-Feldstein, J., & Scaglioni, P. P. (2012). The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA. Cancer research, 72(9), 2275-2284. https://doi.org/10.1158/0008-5472.CAN-11-3159