title: Identification of PRKDC (Protein Kinase, DNA-Activated, Catalytic Polypeptide) as an essential gene for colorectal cancer (CRCs) cells.
abstract: Oncogene and non-oncogene addictions describe the phenomenon that tumor cells become reliant on certain genes for maintenance of malignancy. Reversal of these mutations profoundly affects tumor growth and survival, providing a fundamental rationale for development of targeted cancer therapy. However, inadequate knowledge on cancer signaling networks and lack of potential drug targets limited its clinical application. A screen was conducted using a custom small interfering RNA (siRNA) library in colorectal cancer (CRC). Transient knockdown followed by cell proliferation assays were performed to validate the essentiality of PRKDC (Protein Kinase, DNA-Activated, Catalytic Polypeptide) in CRC. Western blot analysis was performed to examine the mechanism by which PRKDC confers selective survival advantage in CRC cells. Inducible knockdown and overexpression cell lines were introduced into nude mice to assess PRKDC dependency of CRC cells in vivo. PRKDC expression level in patient samples and overall survival of patients with low or high PRKDC expression were analyzed. Transient knockdown of PRKDC reduced cell proliferation/survival in HCT116 and DLD1, but not FHC cells. PRKDC down-regulation induced apoptosis partially through inhibiting AKT activation, and sensitized HCT116 cells to chemotherapeutic agents interfering with DNA replication. Inducible knockdown of PRKDC inhibited tumor growth in vivo. PRKDC was up-regulated in cancerous tissues compared with normal tissues. Patients with high PRKDC expression showed poorer overall survival. PRKDC is an essential gene required for CRC cell proliferation/survival, which may represent as a potential prognostic biomarker and an ideal therapeutic target for CRC.
authors.affiliation: The Central Hospital of Zaozhuang Mining Group of Shandong, Qilianshan Road, High-tech Zone, Zaozhuang 277800, Shandong, China. Electronic address: shangfengsun@126.com.
authors.forename: Shangfeng
authors.initials: S
authors.lastname: Sun
authors.affiliation: The Central Hospital of Zaozhuang Mining Group of Shandong, Qilianshan Road, High-tech Zone, Zaozhuang 277800, Shandong, China.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Cheng
authors.affiliation: The Central Hospital of Zaozhuang Mining Group of Shandong, Qilianshan Road, High-tech Zone, Zaozhuang 277800, Shandong, China.
authors.forename: Yunxiao
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: The Central Hospital of Zaozhuang Mining Group of Shandong, Qilianshan Road, High-tech Zone, Zaozhuang 277800, Shandong, China. Electronic address: pengzhangg@139.com.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Information Technology, Jining Medical University, Hehua Road, Jining 272067, Shandong, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Guhuai Road, Jining 272029, Shandong, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Xu
authors.affiliation: Central Laboratory, Second Hospital of Shandong University, Jinan 250014, Shandong, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of General Surgery, Second Hospital of Shandong University, Jinan 250014, Shandong, China.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Lv
mesh_terms: D000818:Animals; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D051747:DNA-Activated Protein Kinase / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D020043:Genes, Essential; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics*; D034741:RNA, Small Interfering; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human
keywords: AKT; Colorectal cancer; PRKDC; siRNA screen