PRDM16 Drives Thyroid Cancer Differentiation via a TRIM58-MVP Axis to Suppress MAPK and PI3K/AKT Signaling.

Thyroid cancer frequently undergoes dedifferentiation, progressing into poorly differentiated or anaplastic carcinoma, which is characterized by therapeutic resistance and a poor prognosis. Epigenetic dysregulation, particularly histone methylation, plays a critical role in this process. In this study, we identify PRDM16 as an essential regulator of thyroid cancer differentiation. Mechanistically, we demonstrate that PRDM16 catalyzes H3K9 monomethylation at the TRIM58 promoter region, thereby enhancing TRIM58 transcription. Upregulated TRIM58 subsequently promotes ubiquitination and degradation of MVP, leading to suppression of both the MAPK and PI3K/AKT signaling pathways and maintenance of cellular differentiation. This PRDM16-TRIM58-MVP axis modulates proliferation, epithelial-mesenchymal transition, and radioiodine uptake in thyroid cancer cells. Moreover, PRDM16 overexpression enhances the efficacy of MAPK inhibitor-induced redifferentiation therapy. Collectively, these findings establish PRDM16 as a novel tumor suppressor and potential therapeutic target, offering a promising redifferentiation-based strategy for the treatment of advanced thyroid cancer.