Abstract

Decorin-evoked paternally expressed gene 3 (PEG3) represents a critical biomarker in cancer. However, studies on PEG3’s regulation of mitophagy in papillary thyroid carcinoma (PTC) are rare. This study revealed that PEG3 was markedly underexpressed in PTC samples. PEG3 overexpression inhibited cell viability, increased oxidative stress, and resulted in mitochondrial membrane potential loss in PTC cell lines. Notably, PEG3 suppressed mitophagy levels, as evidenced by decreased mitochondria within autophagic structures, reduced LC3B-TOMM20 co-localization, enhanced green fluorescent protein (EGFP) in the COX8-mCherry-EGFP system, and altered expression of mitophagy-related biomarker proteins. Mechanically, PEG3 bound to the Galectin1 promoter and inhibited its transcription in a KAP1-dependent manner. The proliferation and mitophagy inhibition effects of PEG3 were reversed by co-overexpressing Galectin1. Further mechanistic analysis demonstrated that Galectin1 bound to PHB2 and increased its phosphorylation level, which facilitated PHB2-mitochondrion transfer and mitophagy activation. The effect of Galectin1 on PHB2 was mediated through the interaction between DYRK1A and PHB2, leading to enhanced phosphorylation of PHB2 at S39 by DYRK1A. DYRK1A overexpression elevated the phosphorylation level, mitochondrial transfer, and mitophagy-inducing effect of wild-type PHB2 but had no effect on the S39 non-phosphorylation mimic mutation PHB2 (S39A). PHB2 facilitated cell proliferation and PTC mitophagy, which was attenuated by Galectin1 knockdown. In conclusion, Galectin1 was transcriptionally regulated by PEG3/KAP1, subsequently collaborating with DYRK1A to induce the phosphorylation and mitochondrial transfer of PHB2, contributing to enhanced PTC mitophagy and progression.