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Ciliogenesis is often impaired in some cancer cells, leading to acceleration of cancer phenotypes such as cell migration and proliferation. From the investigation of primary cilia of 16 gastric cancer cells (GCs), we found that GCs could be grouped into four primary cilia (PC)–positive GCs and 12 PC-negative GCs. The proliferation of the PC-positive GCs was lower than that of PC-negative GCs. To explore the role of fatty acid binding protein 4 (FABP4), which is a known oncogenic factor, in ciliogenesis, FABP4 expression and function were inhibited by transfection of cells with short interfering RNA targeting FABP4 (siFABP4) or FABP4 inhibitor treatment. Notably, the proliferation and migration of the cilia-forming GCs was effectively suppressed by inhibition of FABP4. In addition, the primary cilia in GCs were restored by a factor greater than two, suggesting a negative role of FABP4 in ciliogenesis in these GCs and FABP4 as a potential anticancer target.

Ciliopathies are clinically overlapping genetic disorders involving structural and functional abnormalities of cilia. Currently, there are no small-molecule drugs available to treat ciliary defects in ciliopathies. Our phenotype-based screen identified the flavonoid eupatilin and its analogs as lead compounds for developing ciliopathy medication. CEP290, a gene mutated in several ciliopathies, encodes a protein that forms a complex with NPHP5 to support the function of the ciliary transition zone. Eupatilin relieved ciliogenesis and ciliary receptor delivery defects resulting from deletion of CEP290. In rd16 mice harboring a blinding Cep290 in-frame deletion, eupatilin treatment improved both opsin transport to the photoreceptor outer segment and electrophysiological responses of the retina to light stimulation. The rescue effect was due to eupatilin-mediated inhibition of calmodulin binding to NPHP5, which promoted NPHP5 recruitment to the ciliary base. Our results suggest that deficiency of a ciliopathy protein could be mitigated by small-molecule compounds that target other ciliary components that interact with the ciliopathy protein.