*3.1. CRL3KCTD17, USP8, and TCHP*

TCHP, a centriolar protein originally identified as a keratin-binding protein, activates AURKA and suppresses ciliogenesis [101,141,142]. TCHP is ubiquitinated by the E3 ligase CRL3KCTD17, a complex of the scaffold protein Cullin 3, RING box protein 1 (RBX1), and potassium channel tetramerization domain-containing 17 (KCTD17) [33]. Knockdown of KCTD17 in RPE1 cells suppresses ciliogenesis by stabilizing TCHP, leading to the activation of AURKA [33]. NDE1-like 1 (NDEL1), a modulator of dynein activity localized at the subdistal appendage of the mother centriole [143,144], indirectly inhibits ubiquitination of TCHP by CRL3KCTD17 [106]. In contrast, TCHP is deubiquitinated by USP8 after EGFR-mediated phosphorylation of USP8 at tyrosine residues 717 and 810 [34]. Knockdown of USP8 in RPE1 cells induces ciliogenesis and cell-cycle arrest even in the presence of serum [34]. These findings sugges<sup>t</sup> that forced ciliogenesis by inhibition of USP8 may be a potential therapeutic strategy for cancers with a high expression of USP8 and loss of cilia. In fact, USP8 is highly expressed and plays an oncogenic role in melanoma [124], and inhibition of USP8 suppresses the proliferation of glioblastoma stem cells [125]. The precise effect of USP8 on ciliogenesis in these tumor cells remains to be elucidated. In zebrafish, knockout of Usp8 increases ciliogenesis in renal tubules and causes renal cysts [34], whereas knockout of Kctd17 impairs ciliogenesis in Kupffer's vesicle and causes

situs inversus (Figure 1). Because AURKA is also associated with both cancer and ciliopathy [95,97], these findings sugges<sup>t</sup> that the involvement of KCTD17 and USP8 in cancer and ciliopathy might be mediated by e ffects on ciliogenesis via a TCHP–AURKA pathway.
