Neoplasia & Endocrine Differentiation, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain.
Dana Farber Cancer Institute, Boston, MA, USA.
Nat Commun. 2024 May 14;15(1):3736. 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.
E3 SUMO 连接酶 PIAS2 在分化型甲状腺癌中高度表达，但在未分化的高死亡率的间变性甲状腺癌（ATC）中表达水平较低。我们在这里表明，用转录的双链 RNA 指导的 RNA 干扰（PIAS2b-dsRNAi）耗尽 PIAS2β 异构体可特异性抑制 ATC 细胞系和患者原代培养物的体外生长，以及患者来源的原位异种移植（oPDX）的体内生长。关键的是，PIAS2b-dsRNAi 不会影响正常或非间变性甲状腺肿瘤培养物（分化型癌、良性病变）或细胞系的生长。PIAS2b-dsRNAi 对其他间变性人类癌症（胰腺、肺和胃）也具有抗癌作用。从机制上讲，PIAS2b 是适当的有丝分裂纺锤体和中心体组装所必需的，并且在 ATC 中是一种剂量敏感的蛋白质。PIAS2b 的耗竭会促进前期的有丝分裂灾难。高通量蛋白质组学揭示蛋白酶体（PSMC5）和纺锤体细胞骨架（TUBB3）是 PIAS2b 在有丝分裂起始时 SUMO 化的直接靶标。这些结果表明 PIAS2b-dsRNAi 是 ATC 和其他侵袭性间变性癌的一种很有前途的治疗方法。
