dsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe

Joana S. Rodrigues, Miguel Chenlo, Susana B. Bravo, Sihara Perez-Romero, Maria Suarez-Fariña, Tomas Sobrino, Rebeca Sanz-Pamplona, Román González-Prieto, Manuel Narciso Blanco Freire, Ruben Nogueiras, Miguel López, Laura Fugazzola, José Manuel Cameselle-Teijeiro () and Clara V. Alvarez ()
Additional contact information
Joana S. Rodrigues: Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), Instituto de Investigación Sanitaria (IDIS)
Miguel Chenlo: Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), Instituto de Investigación Sanitaria (IDIS)
Susana B. Bravo: Complejo Hospitalario Universitario de Santiago de Compostela (CHUS), Servicio Galego de Saúde (SERGAS), Instituto de Investigación Sanitaria de Santiago (IDIS), University of Santiago de Compostela (USC)
Sihara Perez-Romero: Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), Instituto de Investigación Sanitaria (IDIS)
Maria Suarez-Fariña: Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), Instituto de Investigación Sanitaria (IDIS)
Tomas Sobrino: Complejo Hospitalario Universitario de Santiago de Compostela (CHUS), Servicio Galego de Saúde (SERGAS), Instituto de Investigación Sanitaria de Santiago (IDIS), University of Santiago de Compostela (USC)
Rebeca Sanz-Pamplona: Aragon Government and CIBERESP
Román González-Prieto: Universidad de Sevilla - CSIC - Universidad Pablo de Olavide-Junta de Andalucía
Manuel Narciso Blanco Freire: Complejo Hospitalario Universitario de Santiago de Compostela (CHUS), Servicio Galego de Saúde (SERGAS), Instituto de Investigación Sanitaria de Santiago (IDIS), University of Santiago de Compostela (USC)
Ruben Nogueiras: Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), Instituto de Investigación Sanitaria (IDIS)
Miguel López: Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), Instituto de Investigación Sanitaria (IDIS)
Laura Fugazzola: University of Milan
José Manuel Cameselle-Teijeiro: Complejo Hospitalario Universitario de Santiago de Compostela (CHUS), Servicio Galego de Saúde (SERGAS), Instituto de Investigación Sanitaria de Santiago (IDIS), University of Santiago de Compostela (USC)
Clara V. Alvarez: Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), Instituto de Investigación Sanitaria (IDIS)

Nature Communications, 2024, vol. 15, issue 1, 1-30

Abstract: Abstract The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an undifferentiated cancer with high mortality. We show here that depletion of the PIAS2 beta isoform with a transcribed double-stranded RNA–directed RNA interference (PIAS2b-dsRNAi) specifically inhibits growth of ATC cell lines and patient primary cultures in vitro and of orthotopic patient-derived xenografts (oPDX) in vivo. Critically, PIAS2b-dsRNAi does not affect growth of normal or non-anaplastic thyroid tumor cultures (differentiated carcinoma, benign lesions) or cell lines. PIAS2b-dsRNAi also has an anti-cancer effect on other anaplastic human cancers (pancreas, lung, and gastric). Mechanistically, PIAS2b is required for proper mitotic spindle and centrosome assembly, and it is a dosage-sensitive protein in ATC. PIAS2b depletion promotes mitotic catastrophe at prophase. High-throughput proteomics reveals the proteasome (PSMC5) and spindle cytoskeleton (TUBB3) to be direct targets of PIAS2b SUMOylation at mitotic initiation. These results identify PIAS2b-dsRNAi as a promising therapy for ATC and other aggressive anaplastic carcinomas.

Date: 2024
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DOI: 10.1038/s41467-024-47751-1

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