CDK8 phosphorylates SOX2 to maintain stemness of pituitary adenoma.

Pituitary adenomas (PAs) are intracranial tumours with severe clinical complications and increased morbidity. Stem cell-like characteristics play a crucial role in the initiation and progression of PAs. In this study, we identified CDK8 as a critical regulator of stemness in PA tumorigenesis. Immunohistochemical analysis demonstrated that CDK8 expression is elevated in clinical PA samples and correlates significantly with Knosp grades, indicating its potential role in parasellar invasion. Inhibition of CDK8 significantly impaired the self-renewal capacity of patient-derived PA stem-like cells (PASCs), as evidenced by reduced tumoursphere formation. To elucidate the underlying mechanism, we found that CDK8 phosphorylates the pluripotency transcription factor SOX2, thereby disrupting its interaction with the E3 ubiquitin ligase HERC5 and preventing SOX2 degradation through the ubiquitin-proteasome pathway. Moreover, pharmacological inhibition of CDK8 markedly suppressed PA cell proliferation and viability in GH3 and MMQ cell lines, primary human PA cells, and murine xenograft models. These findings revealed a novel regulatory mechanism of PA stemness and provided a promising therapeutic target for PA.