ZIC2 affects oral squamous cell carcinoma stemness by regulating glycerophosphocholine metabolism via LYPLA2.

Oral squamous cell carcinoma (OSCC) is a common malignant tumor of the head and neck. Early-stage OSCC is primarily treated using surgery; advanced-stage OSCC is managed using a multidisciplinary approach, including surgery combined with adjuvant radiotherapy and chemotherapy. However, tumor recurrence and metastasis remain major challenges, with a 5-year survival rate of ~50%. Dysregulation of transcription factors is associated with the pathogenesis of various cancers. This study focused on the role of ZIC2, a member of the zinc finger protein family, in OSCC. ZIC2 was identified as a prognostically relevant transcription factor in OSCC through bioinformatic analysis, showing high expression in OSCC and association with poor prognosis in patients. In vitro and in vivo, ZIC2 knockdown inhibited the proliferation, migration, invasion, and spheroid formation ability of OSCC cells and restored their sensitivity to chemotherapeutic drugs; overexpression of ZIC2 showed the opposite effect. RNA-seq and targeted metabolomics analyses revealed that in OSCC cells with zic2 knockdown, the expression of glycerophosphocholine (GPC) and the key rate-limiting enzyme LYPLA2 was decreased. LYPLA2 overexpression rescued the effects of ZIC2 knockdown on the proliferation, migration, and invasion of OSCC cells. GPC increased the stemness of OSCC tumor cells; ZIC2-regulated GPC metabolism through LYPLA2, inducing changes in the expression of the cancer stem cell markers Nanog and OCT4. In conclusion, we identified ZIC2 as an OSCC stemness-related gene, a potential therapeutic target for OSCC, providing new insights for treating OSCC.