Targeting E3 Ubiquitin Ligases and Deubiquitinases in Ciliopathy and Cancer

Abstract

Cilia are antenna-like structures present in many vertebrate cells. These organelles detect extracellular cues, transduce signals into the cell, and play an essential role in ensuring correct cell proliferation, migration, and differentiation in a spatiotemporal manner. Not surprisingly, dysregulation of cilia can cause various diseases, including cancer and ciliopathies, which are complex disorders caused by mutations in genes regulating ciliary function. The structure and function of cilia are dynamically regulated through various mechanisms, among which E3 ubiquitin ligases and deubiquitinases play crucial roles. These enzymes regulate the degradation and stabilization of ciliary proteins through the ubiquitin–proteasome system. In this review, we briefly highlight the role of cilia in ciliopathy and cancer; describe the roles of E3 ubiquitin ligases and deubiquitinases in ciliogenesis, ciliopathy, and cancer; and highlight some of the E3 ubiquitin ligases and deubiquitinases that are potential therapeutic targets for these disorders.

Aurora A and AKT Kinase Signaling Associated with Primary Cilia

“…Knockdown (KD) of TCHP in human RPE cells cultured in the presence of serum inhibits AURKA activation, induces ciliogenesis, and suppresses cell proliferation [ 47 ]; however, the effects on ciliogenesis and proliferation are suppressed by co-KD of intraflagellar transport 20 (IFT20), a protein required for primary cilia assembly [ 47 , 112 ]. These findings clearly demonstrate that ciliogenesis can inhibit the cell cycle and that TCHP–AURKA regulate cell proliferation via their effects on primary cilia [ 30 , 31 , 32 , 33 , 34 , 38 , 74 ] ( Figure 2 A).…”

“…Notably, formation of primary cilia is suppressed in several cancers in which expression of AURKA is increased, including epithelial ovarian cancer [ 63 ], prostate cancer [ 66 ], pancreatic ductal adenocarcinoma [ 57 , 107 ], and glioblastoma [ 108 , 109 ]. These findings suggest that inhibition of AURKA may suppress the proliferation of these cancer cells by promoting ciliogenesis [ 22 , 30 , 31 , 32 , 33 , 34 , 38 , 71 , 74 ]. Various proteins have been identified as modulators of AURKA-mediated disassembly of primary cilia during G1, including trichoplein (TCHP), neural precursor cell expressed developmentally downregulated 9 (NEDD9), and centrosomal protein 55 (CEP55), which we discuss in more detail here ( Figure 2 ).…”

“…KD of KCTD17 and USP8 suppresses and promotes, respectively, the formation of primary cilia in human RPE cells [ 48 , 50 ]. In zebrafish, knockout (KO) of kctd17 impairs ciliogenesis in Kupffer’s vesicle and induces situs inversus [ 74 ], whereas KO of usp8 increases ciliogenesis in the pronephric duct and causes renal cysts [ 50 ]. Dysregulation of AURKA is also associated with situs inversus and polycystic kidney in mice [ 113 , 114 ].…”

“…Furthermore, forced ciliation has been shown to disrupt progression of the cell cycle in proliferating human RPE cells [ 47 , 48 , 49 , 50 ], illustrating the importance of these organelles for proper cell function. The abundance of primary cilia is reduced in a range of cancer types, including glioblastoma [ 51 ], esophageal squamous cell carcinoma [ 52 ], colon cancer [ 53 ], cholangiocarcinoma [ 54 , 55 ], pancreatic ductal adenocarcinoma [ 56 , 57 ], clear cell renal cell carcinoma [ 58 , 59 , 60 , 61 ], epithelial ovarian cancer [ 62 , 63 ], luminally derived breast cancer [ 64 ], prostate cancer [ 65 , 66 ], melanoma [ 67 , 68 ], and chondrosarcoma [ 69 , 70 ], highlighting the importance of negative regulation of the cell cycle and proliferation by primary cilia [ 30 , 31 , 32 , 33 , 71 , 72 , 73 , 74 , 75 , 76 ].…”

Primary cilia and lipid raft dynamics

“…The possibility that primary cilia may take part in lipid raft dynamics [27] provides a novel approach to modulate lipid raft-mediated Akt signalling through targeting primary cilia. Genome-wide screens have identified various ciliary proteins that directly regulate ciliogenesis and the associated proteins that regulate the expression and function of these ciliary proteins [64,66,[112][113][114][115][116][117][118][119]. Multi-omics approaches, including lipidomics and glycomics, can also be used to identify novel components involved in the formation of primary cilia and lipid raft-mediated signalling.…”