New Insights Into the Role of Polo‐Like Kinase 3 in Lung Tumorigenesis

Polo-like kinase 3 (PLK3) plays major roles in cell cycle regulation, DNA repair, and cellular responses to hypoxia. Our prior studies demonstrated that PLK3 negatively regulates the hypoxic response by directly phosphorylating and destabilizing HIF-1α and by destabilizing the E3 ubiquitin ligase SIAH2. We also find that PLK3 stabilizes PTEN by direct phosphorylation. Plk3 knockout mice exhibit increased spontaneous tumorigenesis in multiple organs, particularly the lung, at an advanced age. Tumors from these mice tend to be highly vascularized, consistent with the function of PLK3 in the hypoxic response. However, another study only observed increased tumorigenesis in female Plk3 knockout mice. The present study further explored the role of PLK3 in lung tumorigenesis. We find that PLK3 can phosphorylate SIAH2 in vitro, confirming our hypothesis that PLK3 regulates SIAH2 by direct phosphorylation. We detected a negative correlation between the levels of PLK3 and SIAH2 and a positive correlation between HIF-1α and SIAH2 in both human lung adenocarcinoma and squamous cell carcinoma. We observed an increase in lung tumorigenesis in Plk3 knockout mice in the A/J strain background. Our RNA-Seq analysis revealed significantly increased expression of genes involved in oncogenic pathways and the immune response in lung tumors from Plk3 knockout mice. Finally, we find that induced systemic SIAH2 expression promotes CD8 T cell infiltration into subcutaneous tumors in a syngeneic mouse model. Our work further supports the tumor suppressive role of PLK3 in lung cancer and discovered a novel involvement of PLK3 in the regulation of the immune microenvironment of lung tumors.