The PKA/MBD2 Axis Transcriptionally Represses INPP5A to Modulate PI3K/Akt Signaling and Accelerate Pituitary Tumorigenesis

Context and Objective The malignant progression of pituitary neuroendocrine tumors (PitNETs) is closely associated with abnormalities in the phosphoinositide signaling pathway. This study aims to investigate the regulatory role and molecular mechanism of inositol polyphosphate 5‐phosphatase A (INPP5A) in the malignant progression of PitNETs, with a focus on its interaction with the PI3K/Akt signaling pathway and the epigenetic regulator MBD2. Setting Tongji Hospital of Tongji medical college of Huazhong University of Science and Technology. Design Analyze genes related to IP3 metabolism in single‐cell sequencing samples of PitNETs from NCBI, and perform immunofluorescence staining and statistical analysis on samples from 62 patients with PitNETs. Result INPP5A was significantly downregulated in PitNETs, and its expression was negatively correlated with tumor invasiveness, Ki67 index, and volume, Overexpression of INPP5A inhibited tumor cell proliferation, migration, and hormone secretion, while knockdown of INPP5A promoted these malignant phenotypes, INPP5A negatively regulated the PI3K/Akt pathway by degrading IP3, MBD2 directly bound to the INPP5A promoter region to mediate transcriptional repression, Activation of PKA signaling phosphorylated MBD2 (at S99), recruited 14‐3‐3σ to stabilize the MBD2 protein, and enhanced the inhibition of INPP5A. Conclusion INPP5A acts as a tumor suppressor gene in PitNETs, and its downregulation promotes tumor malignant progression by activating the PI3K/Akt pathway. MBD2 and its PKA‐mediated phosphorylation are key mechanisms for INPP5A transcriptional repression. Targeting the MBD2‐INPP5A‐PI3K/Akt axis may provide a new strategy for the treatment of PitNETs.