SOX12 promotes serine synthesis and tumor progression in endometrial cancer.

Studies have demonstrated that the sex-determining region Y-box 12 (SOX12), a key oncogene, is highly expressed in various tumors and is associated with poor prognosis. Unfortunately, the effect of SOX12 in endometrial cancer (EC) remains unclear. Here, we discovered that SOX12 expression was significantly elevated in EC tissues from advanced-stage patients and patients who died. Additionally, high expression of SOX12 was shown to predict poor overall survival (OS) and recurrence-free survival (RFS), indicating that SOX12 is an independent prognostic factor for patients with EC. Furthermore, the overexpression or knockdown of SOX12 significantly enhanced or inhibited the activity, proliferation, migration, invasion ability, serine synthesis pathway (SSP) activity and metabolism, respectively, of EC cells. Moreover, overexpression of SOX12 significantly promoted the growth and malignant progression of subcutaneously transplanted tumors, facilitated the formation of lung metastatic nodules, and ultimately reduced the survival time of nude mice. In contrast, stable suppression of SOX12 markedly inhibited the growth of subcutaneous grafts and the formation of lung metastatic nodules in introduced via the tail vein, while also increasing the survival time of nude mice. Mechanistically, SOX12 directly binds to the promoter of the target gene 3-phosphoglycerate dehydrogenase (PHGDH), activating its transcription and enhancing the SSP and metabolism, which ultimately contributes to the malignant progression of EC. Surprisingly, we found that the combination of serine deprivation and SOX12 knockdown had a more pronounced effect on inhibiting the malignant progression of EC in vivo and in vitro. In summary, our study not only enhances the understanding of the carcinogenic mechanisms associated with SOX12 but also presents a potential strategy for molecularly targeted therapy in EC.