SHMT2 promotes thyroid cancer metastasis through epigenetic activation of AKT signaling

Abstract Cancer cells alter their metabolism and epigenetics to support cancer progression. However, the key modulator connecting metabolism and epigenetics is still limited. Here, we reveal that SHMT2 generates SAM to epigenetically repress PTEN, leading to thyroid cancer metastasis depending on activation of AKT signaling. SHMT2 is elevated in thyroid cancer, which cooperates with poor prognosis. Overexpressed SHMT2 promotes thyroid cancer metastasis both in vitro and in vivo . Proteomic enrichment analysis shows that AKT signaling is activated in thyroid cancer, which is positively associated with SHMT2 in specimens from patients. Blocking AKT activation eliminates effects of SHMT2 on promoting thyroid cancer metastasis. Furthermore, SHMT2 is negatively associated with AKT negative regulator PTEN in THCA specimens. Mechanistically, SHMT2 catalyzes serine metabolism and produces activated one-carbon units that can be used to generate SAM for methylation of CpG islands in PTEN promoter for PTEN suppression and following AKT activation. Importantly, interfering PTEN expression affects SHMT2 functions on promoting AKT signaling activation and thyroid cancer metastasis. Collectively, our research demonstrates that SHMT2 connects metabolic reprogramming and epigenetics, which contributes to poor progression of thyroid cancer.