Expression, regulating mechanism and therapeutic target of KIF20A in multiple cancer

Abstract

Kinesin family member 20A (KIF20A) is a member of the kinesin family. It transports chromosomes during mitosis, plays a key role in cell division. Recently, studies proved that KIF20A was highly expressed in cancer. High expression of KIF20A was correlated with poor overall survival (OS). In this review, we summarized all the cancer that highly expressed KIF20A, described the role of KIF20A in cancer. We also organized phase I and phase II clinical trials of KIF20A peptides vaccine. All results indicated that KIF20A was a promising therapeutic target for multiple cancer.

Keywords: ATP, adenosine triphosphate; BTC, biliary tract cancer; CPC, chromosomal passenger complex; CTL, cytotoxic T lymphocyte; Cancer; Cdk1, cyclin-dependent kinase 1; DLG5, discs large MAGUK scaffold protein 5; EMT, epithelial-mesenchymal transition; Expression; FoxM1, forkhead box protein M1; GC, gastric cancer; GEM, gemcitabine; Gli2, glioma-associated oncogene 2; HLA, human leukocyte antigen; HNMT, head-and-neck malignant tumor; IRF, interferon regulatory factor; JAK, Janus kinase; KIF20A; KIF20A, kinesin family member 20A; LP, long peptide; MHC I, major histocompatibility complex I; MKlp2, mitotic kinesin-like protein 2; Mad2, mitotic arrest deficient 2; OS, overall survival; PBMC, peripheral blood mononuclear cell; Plk1, polo-like kinase 1; Regulating mechanisms; Therapeutic target; circRNA, circular RNA; miRNA, microRNA.

Fig. 1

The structure of KIF20A. A. KIF20A consists of three functional domains: a N-terminal motor domain that mediates motor activity, a central helical domain containing Rab6 and myosin II binding domain, which is essential for dimerization and interaction with partner proteins, and a C-terminal tail domain that contributes to vesicle transport and interaction with partner proteins. B. N-terminal motor domain interacts with microtubules at the presence of ATP, ATP provides energy to force KIF20A move toward to the positive end of the microtubule. C-terminal tail domain contributes to vesicle transport and interaction with cargo. C. 3D structure of KIF20A. Structure data was extracted from RCSB PDB (https://www.rcsb.org/).

Fig. 2

KIF20A in mitosis and tumor proliferation. A. KIF20A participates in cell division. During the interphase of the cell cycle, KIF20A co-located with Myosin II at the Golgi division hotspot to regulate the division process of Rab6-positive vesicles. In prophase, KIF20A accumulated in the nucleus, then Myosin II recruited KIF20A into the equatorial cortex before entry furrow ingression. In metaphase, as the nucleus disappears, KIF20A appears in the cytoplasm. In anaphase, chromosomal passenger complex (CPC: complex of Aurora B, INCENP, survivin and borealin) and KIF20A form a complex, which is located in the cleavage furrow and promotes the formation of cleavage furrow, and this process is mediated by decreased Cdk1 activity. In late mitosis, KIF20A mediates spindle formation. Plk1 form a complex with KIF20A and phosphorylates it, thus regulates the binding of KIF20A to microtubules. Phosphorylation of KIF20A by Plk1 is necessary for the spatial restriction of Plk1 to the central spindle during anaphase and telophase. Mad2 is a negative regulator of KIF20A. At early stage of mitosis, Mad2 negatively regulates the load of KIF20A onto the mitotic spindle. At late stage of mitosis, the localization of KIF20A at the cytokinesis of CPC is also reduced by Mad2. B. Proteins that interact with KIF20A, only physical interactions were preserved. The interaction data was extracted from GENEMANIA (https://genemania.org/). C. In glioma cancer, KIF20A contributed cytokinesis and generation of binucleated cells; in breast cancer and gastric cancer, KIF20A arrested cells at the G2/M phase; in hepatocellular carcinoma, KIF20A affected cell transition from G1 to S phase through E2F1.

Fig. 3

The expression of KIF20A in normal tissues and cancers. Expression results were generated with GEPIA 2 (http://gepia2.cancer-pku.cn/).

Fig. 4

High expressed KIF20A predicted a poor OS. Data from TCGA databases. A. Kidney renal clear cell carcinoma. B. Bladder Carcinoma. C. Breast cancer. D. Cervical squamous cell carcinoma. E. Esophageal Adenocarcinoma. F. Esophageal Squamous Cell Carcinoma. G. Head-neck squamous cell carcinoma. H. Kidney renal papillary cell carcinoma. I. Lung squamous cell carcinoma. J. Liver hepatocellular carcinoma. K. Lung adenocarcinoma. L. Ovarian cancer. M. Rectum adenocarcinoma. N. Pancreatic ductal adenocarcinoma. O. Pheochromocytoma and Paraganglioma. P. Uterine corpus endometrial carcinoma. Q. Sarcoma. R. Stomach adenocarcinoma. S. Testicular Germ Cell Tumor. T. Thymoma. U. Thyroid carcinoma.

Fig. 5

KIF20A genome was altered in multiple cancers. Data from http://www.cbioportal.org/.

Fig. 6

KIF20A regulated cancer via JAK-STAT3 and Hh signaling pathways. In colorectal cancer, increased KIF20A promoted cell proliferation through activated JAK-STAT3; in glioma, miR-876-3p suppressed KIF20A, inhibited JAK2-STAT3 signaling pathway; in hepatocellular carcinoma, KIF20A was a target of Hh signaling, Gli2 enhanced KIF20A by FoxM1, increased KIF20A promoted HCC growth and survival.

Fig. 7

KIF20A was a target of circRNA in facilitating cancer. A. In cervical cancer, circ_0005576 and UCA1 acted as sponges of miR-153-3p and miR-204 to increase KIF20A; in glioma, circRNA-Serpine2 upregulated KIF20A expression by sponging miR-124–3p. Increased KIF20A accelerated the proliferation, invasion, migration, and inhibited apoptosis of cancer cells. B. lncRNA-miRNA-KIF20A network. The KIF20A-miRNA targets were predicted with TargetScanHuman (https://www.targetscan.org/vert_71/) and the miRNA-lncRNA targets were predicted with ENCORI (https://www.targetscan.org/vert_71/), the network was generated with Cytoscape (v 3.9.1).