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

• Published in: Nature communications 2024-05, Vol.15 (1), p.3736-30, Article 3736
• Main Authors: Rodrigues, Joana S., Chenlo, Miguel, Bravo, Susana B., Perez-Romero, Sihara, Suarez-Fariña, Maria, Sobrino, Tomas, Sanz-Pamplona, Rebeca, González-Prieto, Román, Blanco Freire, Manuel Narciso, Nogueiras, Ruben, López, Miguel, Fugazzola, Laura, Cameselle-Teijeiro, José Manuel, Alvarez, Clara V.
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/31; 13/89; 14/19; 14/5; 38/23; 38/35; 38/70; 38/77; 38/88; 42; 42/44; 631/337/641/1655; 631/67/1459/1843; 692/4028/67/1059; 82/1; 82/51; 82/58; 82/80; 82/83; Animals; Assembly; Cancer; Carcinoma - genetics; Carcinoma - metabolism; Carcinoma - pathology; Cell differentiation; Cell Line, Tumor; Cytoskeleton; Depletion; Double-stranded RNA; Female; Humanities and Social Sciences; Humans; Mice; Mitosis; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; multidisciplinary; Pancreas; Papillary thyroid carcinoma; Prophase; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein Inhibitors of Activated STAT - genetics; Protein Inhibitors of Activated STAT - metabolism; Proteomics; RNA Interference; RNA-mediated interference; Science; Science (multidisciplinary); Spindle Apparatus - metabolism; SUMO protein; Sumoylation; Therapeutic targets; Thyroid; Thyroid cancer; Thyroid gland; Thyroid Neoplasms - genetics; Thyroid Neoplasms - metabolism; Thyroid Neoplasms - pathology; Tumor cell lines; Ubiquitin-protein ligase; Xenograft Model Antitumor Assays; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47751-1

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. Anaplastic thyroid cancer (ATC) is a particularly aggressive cancer type with limited effective therapeutic options. Here, the authors identify the SUMO E3 ligase PIAS2 as a potential therapeutic target in ATC and mechanistically investigate its role in mitotic spindle and centrosome assembly.