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Yu-Chia Chen,1,* I-shu Chen,1,* Guan-Jin Huang,2 Chi-hsiang Kang,1 Kuo-Chiang Wang,1 Min-Jen Tsao,3 Hung-Wei Pan4,5 1Department of Surgery, Division of General Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; 2Department of Pathology, National Chung Kung University Hospital, Tainan, Taiwan; 3Department of General Surgery, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan; 4Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; 5Department of Applied Chemistry, National Pingtung University, Pingtung, Taiwan *These authors contributed equally to this work Background: Hepatocellular carcinoma (HCC) has an increasing incidence and high mortality. Surgical operation is not a comprehensive strategy for liver cancer. Moreover, tolerating systemic chemotherapy is difficult for patients with HCC because hepatic function is often impaired due to underlying cirrhosis. Therefore, a comprehensive strategy for cancer treatment should be developed. DTL (Cdc10-dependent transcript 2) is a critical regulator of cell cycle progression and genomic stability. In our previous study, the upregulation of DTL expression in aggressive HCC correlated positively with tumor grade and poor patient survival. We hypothesize that targeting DTL may provide a novel therapeutic strategy for liver cancer. DTL small interference RNAs were used to knock down DTL protein expression.Methods: A clonogenic assay, immunostaining, double thymidine block, imaging flow cytometry analysis, and a tumor spheroid formation assay were used to analyze the role of DTL in tumor cell growth, cell cycle progression, micronucleation, ploidy, and tumorigenicity.Results: Our results demonstrated that targeting DTL reduced cell cycle regulators and chromosome segregation genes, resulting in increased cell micronucleation. DTL depletion inhibited liver cancer cell growth, increased senescence, and reduced tumorigenesis. DTL depletion res