Article
dsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe
Author/s | Rodrigues, Joana S.
Chenlo, Miguel Bravo, Susana B. Pérez Romero, Sihara Suárez Fariña, María Sobrino, Tomás Sanz Pamplona, Rebeca González Prieto, Román Álvarez, Clara V. |
Department | Universidad de Sevilla. Departamento de Biología Celular |
Publication Date | 2024-05-14 |
Deposit Date | 2024-06-10 |
Published in |
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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 ... 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. |
Funding agencies | Agencia Estatal de Investigación. España Instituto de Salud Carlos III |
Project ID. | BFU2013-46109-R
BFU2016-76973-R PID2019-110437RB-I00 PDC2021-121621-I00 PID2022-140149OB-I00 ISCIII-PI23/00722 PI19/01316 CPII17/00027 |
Citation | Rodrigues, J.S., Chenlo, M., Bravo, S.B., Pérez Romero, S., Suárez Fariña, M., Sobrino, T.,...,Álvarez, C.V. (2024). dsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe. Nature Communications, 15 (1), 3736. https://doi.org/10.1038/s41467-024-47751-1. |
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