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

Research output: Contribution to journalArticle

55 Citations (Scopus)

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

Fingerprint

Sumoylation
Acute Promyelocytic Leukemia
Ubiquitin-Protein Ligases
Ubiquitin
Non-Small Cell Lung Carcinoma
Small Ubiquitin-Related Modifier Proteins
Neoplasms
Oncogene Proteins
Leukemia
Phosphorylation
Apoptosis
Cell Line
Proteins
arsenic trioxide
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA. / Rabellino, Andrea; Carter, Brandon; Konstantinidou, Georgia; Wu, Shwu Yuan; Rimessi, Alessandro; Byers, Lauren A.; Heymach, John V.; Girard, Luc; Chiang, Cheng Ming; Teruya-Feldstein, Julie; Scaglioni, Pier Paolo.

In: Cancer Research, Vol. 72, No. 9, 01.05.2012, p. 2275-2284.

Research output: Contribution to journalArticle

Rabellino, A, Carter, B, Konstantinidou, G, Wu, SY, Rimessi, A, Byers, LA, Heymach, JV, Girard, L, Chiang, CM, Teruya-Feldstein, J & Scaglioni, PP 2012, 'The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA', Cancer Research, vol. 72, no. 9, pp. 2275-2284. https://doi.org/10.1158/0008-5472.CAN-11-3159
Rabellino, Andrea ; Carter, Brandon ; Konstantinidou, Georgia ; Wu, Shwu Yuan ; Rimessi, Alessandro ; Byers, Lauren A. ; Heymach, John V. ; Girard, Luc ; Chiang, Cheng Ming ; Teruya-Feldstein, Julie ; Scaglioni, Pier Paolo. / The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA. In: Cancer Research. 2012 ; Vol. 72, No. 9. pp. 2275-2284.
@article{f37420f9c83a4584b99fcfa7e3498dfa,
title = "The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA",
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.",
author = "Andrea Rabellino and Brandon Carter and Georgia Konstantinidou and Wu, {Shwu Yuan} and Alessandro Rimessi and Byers, {Lauren A.} and Heymach, {John V.} and Luc Girard and Chiang, {Cheng Ming} and Julie Teruya-Feldstein and Scaglioni, {Pier Paolo}",
year = "2012",
month = "5",
day = "1",
doi = "10.1158/0008-5472.CAN-11-3159",
language = "English (US)",
volume = "72",
pages = "2275--2284",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA

AU - Rabellino, Andrea

AU - Carter, Brandon

AU - Konstantinidou, Georgia

AU - Wu, Shwu Yuan

AU - Rimessi, Alessandro

AU - Byers, Lauren A.

AU - Heymach, John V.

AU - Girard, Luc

AU - Chiang, Cheng Ming

AU - Teruya-Feldstein, Julie

AU - Scaglioni, Pier Paolo

PY - 2012/5/1

Y1 - 2012/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84860526509&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860526509&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-11-3159

DO - 10.1158/0008-5472.CAN-11-3159

M3 - Article

VL - 72

SP - 2275

EP - 2284

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 9

ER -