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.
Highlights
Multiple biomarkers have been identified to assist in disease diagnosis and predict treatment efficacy and patient outcomes for cancers such as colorectal cancer (CRC) (Oh and Joo, 2020)
Immunohistochemical staining analyses revealed that PDZ-binding kinase (PBK) expression showed a significant correlation to phosphohistone H3 (PHH3) expression in CRC cells (ρ 0.238, p < 0.0001, Figure 1A)
We showed the significant association between PBK and PHH3 expressions in CRC, both of which are favorable factors for the survival of CRC patients (Koshino et al, 2021; Nagano-Matsuo et al, 2021)
Summary
Multiple biomarkers have been identified to assist in disease diagnosis and predict treatment efficacy and patient outcomes for cancers such as colorectal cancer (CRC) (Oh and Joo, 2020) Cellular proliferation markers such as Ki-67 have been widely used as biomarkers to predict recurrence, treatment response, and prognosis of patients with many types of cancers (Tao et al, 2017; Ahn et al, 2018; Poulakaki et al, 2018; Menon et al, 2019; Xiong et al, 2019). Our group identified two cellular proliferation-associated markers predicting favorable survival for CRC patients; one is PDZ-binding kinase (PBK) (Nagano-Matsuo et al, 2021), and the other is phosphohistone H3 (PHH3) (Koshino et al, 2021). We identified high PBK expression in tumor cells as one of the potential favorable factors for CRC patients (Nagano-Matsuo et al, 2021)
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