PBK Enhances Cellular Proliferation With Histone H3 Phosphorylation and Suppresses Migration and Invasion With CDH1 Stabilization in Colorectal Cancer.
PBK Enhances Cellular Proliferation With Histone H3 Phosphorylation and Suppresses Migration and Invasion With CDH1 Stabilization in Colorectal Cancer.
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DOI：
10.3389/fphar.2021.772926
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发表时间：
2021
影响因子：
5.6
通讯作者：
Inaguma S
中科院分区：
文献类型：
--
作者：
Koshino A;Nagano A;Ota A;Hyodo T;Ueki A;Komura M;Sugimura-Nagata A;Ebi M;Ogasawara N;Kasai K;Hosokawa Y;Kasugai K;Takahashi S;Inaguma S
结直肠癌（Colorectal cancer，CRC）是最常见的胃肠道恶性肿瘤之一，发病率和死亡率都很高。有几种生物标志物可用于阐明CRC的患者结局。最近，我们的研究小组确定了两个有利于CRC患者生存的因素：PDZ结合激酶（PBK）和磷酸化组蛋白H3（PHH 3）。两者均与pT分期呈显着负相关。本研究的目的是揭示这些细胞增殖相关蛋白表达导致结直肠癌患者良好临床结局的机制。我们首先证实了PI 3 K和PHH 3在CRC细胞中的共表达。进一步研究表明，异常表达的PI 3 K上调CRC细胞的细胞增殖，并伴随PHH 3的积累。PI 3 K抑制剂OTS 514通过下调PHH 3和诱导凋亡抑制CRC细胞的细胞增殖。体外研究显示，PBK通过抑制Wnt/β-catenin信号传导和稳定CDH 1来抑制CRC细胞的迁移和侵袭。外源性PBK上调培养细胞中S840、S846和S847残基磷酸化的CDH 1。重组PBK直接磷酸化HH 3;然而，它不能在体外直接磷酸化CDH 1。本研究证实了两种标志物PBK和PHH 3在CRC中的关联。我们进一步确定了这些细胞增殖相关蛋白的更高表达导致CRC患者更好生存的潜在机制之一，这可能涉及PBMC介导的CRC细胞迁移和侵袭的抑制。我们的研究结果表明，PBK靶向治疗可能有助于治疗患有表达PBK的肿瘤的CRC患者。
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.
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