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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Anaplastic thyroid carcinoma (ATC) is an aggressive cancer with high mortality.
• The E3 SUMO ligase PIAS2 is highly expressed in differentiated thyroid cancers but lowly in ATC.
• PIAS2 has distinct isoforms, including PIAS2 beta.

Purpose of the Study:

• To investigate the therapeutic potential of targeting the PIAS2 beta isoform in ATC.
• To elucidate the mechanism by which PIAS2 beta influences ATC cell growth.

Main Methods:

• Utilized transcribed double-stranded RNA-directed RNA interference (dsRNAi) to deplete PIAS2 beta (PIAS2b-dsRNAi).
• Assessed the effect of PIAS2b-dsRNAi on ATC cell lines, patient primary cultures, and orthotopic patient-derived xenografts (oPDX) in vitro and in vivo.
• Examined the impact on normal thyroid cells and non-anaplastic thyroid tumors.
• Investigated PIAS2b's role in mitotic spindle and centrosome assembly using high-throughput proteomics.

Main Results:

• PIAS2b-dsRNAi specifically inhibited the growth of ATC cell lines and patient cultures.
• PIAS2b-dsRNAi demonstrated efficacy in vivo in oPDX models of ATC.
• No adverse effects on normal or non-anaplastic thyroid tissues were observed.
• PIAS2b-dsRNAi exhibited anti-cancer effects in other anaplastic human cancers (pancreas, lung, gastric).
• PIAS2b is essential for mitotic spindle and centrosome assembly, acting as a dosage-sensitive protein in ATC.
• PIAS2b depletion induced mitotic catastrophe at prophase.
• Proteasome subunit PSMC5 and TUBB3 were identified as direct targets of PIAS2b SUMOylation.

Conclusions:

• PIAS2 beta is a critical regulator of ATC cell proliferation and survival.
• PIAS2b-dsRNAi represents a targeted and effective therapeutic strategy for ATC.
• The findings suggest PIAS2b-dsRNAi could be a valuable treatment for other aggressive anaplastic carcinomas.