Insights into a Crucial Role of TRIP13 in Human Cancer

Abstract

Thyroid Hormone Receptor Interacting Protein 13 (TRIP13) plays a key role in regulating mitotic processes, including spindle assembly checkpoint and DNA repair pathways, which may account for Chromosome instability (CIN). As CIN is a predominant hallmark of cancer, TRIP13 may act as a tumor susceptibility locus. Amplification of TRIP13 has been observed in various human cancers and implicated in several aspects of malignant transformation, including cancer cell proliferation, drug resistance and tumor progression. Here, we discussed the functional significance of TRIP13 in cell progression, highlighted the recent findings on the aberrant expression in human cancers and emphasized its significance for the therapeutic potential.

Keywords: CIN; Cancer; Oncogenes; TRIP13.

Graphical abstract

Fig. 1

Biological information for human TRIP13 gene. It is located on the short arm p15 of chromosome 5 (top pannel). The encoded protein have the N-terminal domain, putatively involved in substrate recognition, and AAA+ ATPase region which consists of large and small subdomains. The ATP binding site includes Walker A motif (GxxxxGK[T/S]) and Walker B motif (hhhh[D/E], where h is a hydrophobic residue), and numbers above the structures indicate amino acid residue positions. The 3D structures of TRIP13 protein (PDB:5WC2) bound with ADP as well as hexameric TRIP13 complex (PDB: 6F0X) with ligands and partners are illustrated (bottom pannel).

Fig. 2

Model for the roles of TRIP13 in disassembling the mitotic checkpoint complex (MCC) and in promoting mitotic progression. Unattached kinetochores contribute to the formation of MCC and spindle-assembly checkpoint (SAC) activation. Upon SAC activation, MCC is produced and diffuses into the cytosol to bind and inhibit APC/C^Cdc20. The SAC signal is negatively regulated by chromosome bi-orientation. During checkpoint silencing, the production of MCC is attenuated due to the binding of p31^comet to C-Mad2 in MCC and displaces BubR1–Bub3 from MCC. TRIP13 then disassembles the C-Mad2/Cdc20 complex together with p31^comet, and converts Cdc20-bound C-Mad2 to O-Mad2. Furthermore, TRIP13 and p31^comet preferentially catalyze the disassembly of free MCC that not bound to APC/C^Cdc20. Alternatively, APC15-mediated conformational changes of the APC/C can allow ubiquitination of Cdc20 in MCC, followed by reactivation of APC/C^Cdc20. Collectively, the above mechanisms reduce the MCC levels and promote the activation of APC/C^Cdc20 which ubiquitinates securin and cyclin B1 to inactivate CDK 1 (allowing for mitotic exit) and liberate the protease separase to initiate the onset of anaphase.

Fig. 3

High TRIP13 expression in tumor tissues compared with normal tissues (A-H) and its high expression linked to a poor prognosis in multiple cancers (I—O). (A-H)TRIP13-expression in cancer tissues (T) is compared with normal counterpart tissues (N), including breast invasive carcinoma (A), cervical squamous cell carcinoma, endocervical adenocarcinoma (B), colon adenocarcinoma (C), esophageal carcinoma (D), glioblastoma multiforme (E), head and neck squamous cell carcinoma (F), stomach adenocarcinoma (G) and thymoma (H). TRIP13 expression is significantly higher in all tumors examined (p < .05). (I—O) Kaplan-Meier analyses of OS revealed that high TRIP13 expression conferred inferior outcomes in kidney renal clear cell carcinoma (I), kidney renal papillary cell carcinoma (J), brain lower grade glioma (K), liver hepatocellular carcinoma (L), lung adenocarcinoma (M), ovarian serous cystadenocarcinoma (N), skin cutaneous melanoma (O). Above tumor/normal differential expression analysis and patient survival analysis are from TCGA and GTEx projects and mining using GEPIA tools (http://gepia.cancer-pku.cn) with a standard pipeline compatible with each other.