PBK Enhances Cellular Proliferation With Histone H3 Phosphorylation and Suppresses Migration and Invasion With CDH1 Stabilization in Colorectal Cancer

Abstract

Colorectal cancer (CRC) is one of the most frequent gastrointestinal malignancies with high morbidity and mortality rates. Several biological markers for the prognostication of patient outcome of CRCs are available. Recently, our group identified two favorable factors for the survival of CRC patients: PDZ-binding kinase (PBK) and phospho-histone H3 (PHH3). Both showed a significant inverse association to pT stage. The aim of this study was to uncover the mechanism through which these cellular proliferation–associated protein expressions lead to favorable clinical outcome in CRC patients. We first confirmed co-expression of PBK and PHH3 in CRC cells. Further investigation showed that aberrantly expressed PBK up-regulated the cellular proliferation of CRC cells with accumulation of PHH3. The PBK inhibitor OTS514 suppressed cellular proliferation of CRC cells through down-regulation of PHH3 and induction of apoptosis. In vitro studies revealed that PBK suppressed the migration and invasion of CRC cells with suppression of Wnt/β-catenin signaling and CDH1 stabilization. Exogeneous PBK up-regulated the phosphorylated CDH1 at S840, S846, and S847 residues in cultured cells. Recombinant PBK directly phosphorylated HH3; however, it failed to phosphorylate CDH1 directly in vitro. The present study demonstrated the association of two markers PBK and PHH3 in CRC. We further identified one of the potential mechanisms by which higher expression of these cellular proliferation–associated proteins leads to the better survival of CRC patients, which likely involves PBK-mediated suppression of the migration and invasion of CRC cells. Our findings suggest that PBK-targeting therapeutics may be useful for the treatment of CRC patients with PBK-expressing tumors.

SPATA18 Expression Predicts Favorable Clinical Outcome in Colorectal Cancer

“…Recently, our group revealed that higher expression of PHH3, which is expressed in late G2 and M phases, is associated with lower pT stage and favorable clinical outcome in CRC patients [ 4 ]. These observations were partly explained by our additional in vitro study in which PBK (also known as TOPK) was demonstrated to accelerate cellular proliferation with direct phosphorylation of HH3 (histone H3) along with the suppression CRC cell migration and invasion [ 33 ]. In the present study, SPATA18-high CRCs showed higher PHH3 counts and CCNA labeling indexes than SPATA18-low tumors with favorable clinical outcomes.…”

Topical application of TOPK inhibitor OTS514 suppresses psoriatic progression by inducing keratinocytes cell cycle arrest and apoptosis

“…33 OTS514 and OTS964 have been reported to significantly suppress the growth and metastasis of a variety of human cancer cells. 31,32,[41][42][43] Besides, in pre-clinical models, OTS514 showed potent anti-myeloma activity. 43 In addition to these three TOPK inhibitors, our previous study also identified a novel TOPK inhibitor, paeonol, which is an active compound isolated from traditional Chinese herbs.…”

“…9 Furthermore, it has been reported that inhibiting TOPK by specific inhibitors, OTS514 and OTS964, effectively inhibits the proliferation of many tumour cells. [30][31][32][33] Clinical studies reported that the expression of TOPK was strongly associated with poor prognosis of cancer patients. [34][35][36] As a potential tumour marker, TOPK has attracted extensive attention from basic and clinical researchers.…”

Identification of oncogenes and tumor-suppressor genes with hepatocellular carcinoma: A comprehensive analysis based on TCGA and GEO datasets

“…Frontiers in Genetics frontiersin.org PDZ-binding kinase (PBK) is a serine/threonine kinase belonging to the mitogen-activated protein kinase (MAPK) kinase (MAPKK) family (Sun et al, 2016). Previous studies have shown that PBK is highly trans-activated in various cancers including ovarian cancer (Ma et al, 2022), lymphoma (Wang et al, 2022), kidney cancer (Sun et al, 2022), and colon cancer (Koshino et al, 2022), which is a promising molecular target for cancer-targeted therapy. It is worth mentioning that Yang et al (2019) found that PBK was overexpressed in HCC and was associated with poor prognosis.…”