Research Papers:

The HNF-1β―USP28―Claspin pathway upregulates DNA damage-induced Chk1 activation in ovarian clear cell carcinoma

Fuminori Ito, Chiharu Yoshimoto, Yuki Yamada, Tamotsu Sudo and Hiroshi Kobayashi _

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Oncotarget. 2018; 9:17512-17522. https://doi.org/10.18632/oncotarget.24776

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Fuminori Ito1, Chiharu Yoshimoto1, Yuki Yamada1, Tamotsu Sudo2 and Hiroshi Kobayashi1

1Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan

2Section of Translational Research, Hyogo Cancer Center, Akashi, Hyogo, Japan

Correspondence to:

Hiroshi Kobayashi, email: [email protected]

Keywords: hepatocyte nuclear factor-1β; USP28; claspin; Chk1; DNA damage response

Received: January 02, 2018     Accepted: February 27, 2018     Published: April 03, 2018


Transcription factor hepatocyte nuclear factor 1-beta (HNF-1β) enhances checkpoint kinase 1 (Chk1) activation and promotes G2/M cell cycle progression in ovarian clear cell carcinoma (CCC) following exposure to diverse genotoxic agents including bleomycin. However, the underlying mechanism leading to checkpoint activation of HNF-1β still remains largely unknown. To clarify the effects of HNF-1β on cell cycle checkpoints, human CCC cell lines were transfected with siRNAs targeting HNF-1β, Claspin, USP28, or a control vector. Ubiquitination and stabilization of Claspin protein by HNF-1β was assessed by immunoprecipitation. Loss-of-function studies using RNAi-mediated gene silencing indicated that HNF-1β facilitated the Claspin expression after treatment with a genotoxic agent bleomycin, resulting in accumulation of phosphorylated Chk1 (p-Chk1) and promotion of survival in CCC cell lines. This study showed for the first time that USP28, a de-ubiquitinase crucial for Claspin expression, is one target gene of HNF-1β. Knockdown of endogenous USP28 suppressed the Claspin expression and p-Chk1 activation and cell viability. Our findings identify a novel pathway of the HNF-1β―USP28―Claspin―Chk1 axis in checkpoint signal amplification in response to DNA damage. Targeting this pathway may represent a putative, novel, anticancer strategy in ovarian CCC.

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