Primary cilia function as cell's antenna to sense extracellular signaling and send it into the cell. Once cells exit from cell cycle and go to G0 phase, centrioles, which act as spindle poles in M phase, migrate to the cell surface whereupon a primary cilium is formed. Loss of primary cilia is frequently observed in tumor cells including pancreatic ductal adenocarcinoma (PDAC) cells, leading a notion that absence of the organelle may promote tumorigenesis by aberrant signal transduction and cell cycle. However, molecular mechanisms that explain how PDAC cells lose primary cilia remain unknown. The aim of this project is to clarify the molecular mechanisms underlying suppression of primary ciliogenesis in PDAC cells.

Oncogenic Kras mutations occur in over 90% of PDAC cells and primary cilia formation is repressed by Kras signaling in PDAC cells. Our preliminary data shows that a histone deacetylase, HDAC2, which acts as a transcription regulator, is required for suppression of primary cilia formation in PDAC cells. We also identified a protein that promotes degradation of primary cilia is decreased in HDAC2-depleted PDAC cells. In this project, we will analyze how Kras, HDAC2 and downstream molecules suppress primary cilia formation in PDAC cells.

Pancreatic cancer is the fifth leading cancer killer in Japan and only 6 percent of patients survive 5 years after diagnosis. PDAC is the most frequent type of pancreatic cancer. Our findings in this project could provide new therapeutic approaches to PDAC. In addition, since HDAC2 has not been shown to be involved in primary ciliogenesis, our study may lead to elucidation of novel HDAC2-mediated signaling pathways to regulate primary cilia formation in normal cells as well as in cancer cells.