Primary cilia are evolutionary-conserved, microtubule-based, antennae-like organelles that extrude from the apical surface of the plasma membrane. The fundamental role of primary cilia is to sense and transduce extracellular signals that regulate cell growth and development, such as growth factors and hormones. Primary cilia also serve as the structure checkpoint of the cell cycle. Defects in the formation and/or function of primary cilia cause a wide range of human diseases, including ciliopathies and cancers. Loss of primary cilia commonly associates with various types of cancer, including but not limited to, breast cancer, pancreatic ductal adenocarcinoma, prostate cancer, etc. Cilia loss, although with some exceptions, sensitizes cells to malignant transformation, increases c...[ Read more ]

Primary cilia are evolutionary-conserved, microtubule-based, antennae-like organelles that extrude from the apical surface of the plasma membrane. The fundamental role of primary cilia is to sense and transduce extracellular signals that regulate cell growth and development, such as growth factors and hormones. Primary cilia also serve as the structure checkpoint of the cell cycle. Defects in the formation and/or function of primary cilia cause a wide range of human diseases, including ciliopathies and cancers. Loss of primary cilia commonly associates with various types of cancer, including but not limited to, breast cancer, pancreatic ductal adenocarcinoma, prostate cancer, etc. Cilia loss, although with some exceptions, sensitizes cells to malignant transformation, increases cell proliferation, initiates metastasis and up-regulates oncogenic signaling. However, the molecular mechanisms underlying cilia disassembly and cilia loss in cancer, the molecular linkage between cilia disassembly and cell cycle re-entry, are still largely unknown. The centrosome is the primary microtubule organization center (MTOC) of most animal cells. It plays important roles in numerous biological processes, such as microtubule nucleation and organization, spindle assembly and cell cycle progression. Centrosome amplification results in chromosomal instability (CIN), a common future of many cancers. Nonetheless, how centrosome amplification contributes to tumorigenesis at the molecular level remains unclear.

FOP (FGFR1 Oncogene Partner) is a centrosomal protein and has been implicated in ciliogenesis and cell cycle progression but its roles in cilia disassembly and centrosome duplication are unknown. In the present study, we examined the roles and possible mechanisms of FOP in cilia disassembly and cell cycle re-entry. We demonstrate that, firstly, FOP is a negative regulator of cilia length and essential for timely cilia disassembly. Secondly, FOP promotes cilia shortening through modulating actin network dynamics and upregulating the Aurora A-HDAC6 signaling pathway. Thirdly, FOP facilitates cell cycle re-entry by promoting cilia disassembly. Finally, we show that primary cilia are lost in lung cancer cells. Partial restoration of cilia in H1299 lung cancer cells by knocking down of FOP suppresses anchorage-dependent and -independent cell growth. Taken together, these data suggest that overexpression of FOP contributes to cilia disassembly, thereby accelerating cell cycle re-entry and cell proliferation.

FOP has been shown to localize to the centrosome and centriolar satellites and be upregulated in lung cancer. As a centrosomal protein, the role of FOP in the centrosome is largely unknown, we therefore investigated the centrosome-related roles of FOP. Here, we show that FOP is expressed at high levels in G1 and S phases and low levels in G2 and M phases. The centrosomal localization of FOP, like that of γ-tubulin, is microtubule- and PCM1-independent. Our data also indicate that FOP is required for centriole duplication. Depletion of FOP leads to G1 arrest in a p53-dependent manner. Taken together, these data suggest that deregulation FOP results in centrosome duplication defect and subsequently leads to cell cycle arrest and possibly chromosomal instability, providing an alternative mechanism for the involvement of FOP in cancer development.

To sum up, my study uncovers the roles and molecular mechanisms of FOP in cilia disassembly, cell cycle regulation, and centrosome duplication. Our data support the hypothesis that primary cilia serve as the structure checkpoint of the cell cycle. These findings provide insight into how FOP contributes to tumor progression, and novel target for cancer therapeutics.