# IGF2BP2 Drives Thyroid Cancer Dedifferentiation Through m6A-Dependent STAT1 mRNA Destabilization

## TL;DR

This study identifies IGF2BP2 as a key driver of thyroid cancer dedifferentiation by destabilizing STAT1 mRNA through m6A modification, offering a potential new therapeutic target.

## Contribution

The study reveals a novel mechanism involving IGF2BP2 and m6A-dependent STAT1 mRNA destabilization in thyroid cancer dedifferentiation.

## Key findings

- IGF2BP2 is upregulated in anaplastic thyroid carcinoma and correlates with poor prognosis.
- IGF2BP2 promotes cancer stemness and suppresses thyroid differentiation genes.
- IGF2BP2 binds m6A-modified STAT1 mRNA, accelerating its decay and driving dedifferentiation.

## Abstract

Thyroid cancer is the most common endocrine malignancy globally. While papillary thyroid carcinoma (PTC) typically exhibits favorable prognosis, a subset undergoes dedifferentiation into anaplastic thyroid carcinoma (ATC), an aggressive, treatment-refractory subtype with near-universal lethality. However, the molecular driver of this process remains elusive. In this study, we find that IGF2BP2 is upregulated in ATC and correlates with adverse prognosis. Pseudotime trajectory analysis tracks progressively escalating IGF2BP2 expression throughout dedifferentiation. Functionally, IGF2BP2 promotes proliferation, suppresses thyroid differentiation genes (TSHR, SLC26A4, SLC5A5, TPO, PAX8, FOXE1, and NKX2.1), and enhances cancer stemness. Mechanistically, integrated multi-omics analysis (RNA-seq, RIP-seq, and MeRIP-seq) reveals that IGF2BP2 binds m6A-modified STAT1 mRNA, accelerating its decay. STAT1 directly activates transcription of thyroid differentiation genes. Rescue experiments confirms that STAT1 mediates IGF2BP2-driven dedifferentiation. The IGF2BP2-m6A-STAT1 complex is a master regulator of thyroid cancer dedifferentiation, establishing a novel therapeutic target for redifferentiation therapy in advanced thyroid cancer.