CAMK2N1 suppresses hepatoma growth through inhibiting E2F1-mediated cell-cycle signaling. (28th January 2021)

• Record Type: Journal Article
• Authors: Peng, Jei-Ming; Tseng, Ruo-Han; Shih, Tsung-Chieh; Hsieh, Sen-Yung
• Is Part Of: Cancer letters. Volume 497(2021)
• Page Start: 66
• Page End: 76
• Publication Date: 2021-01-28
• Subjects: Ca2+/calmodulin (CaM)-dependent kinases -- Calcium/calmodulin-dependent protein kinase II inhibitor Alpha -- Cell cycle checkpoints -- Hepatocellular carcinoma -- HCC; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.10.017
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Human kinome/phosphatome screen identified CAMK2N1 genes suppressing the development of human hepatocellular carcinoma (HCC). CAMK2N1 downregulation was found in 47% HCCs and associated with poor prognosis. The downregulation was mainly attributed to its genome deletion (28.4%) and DNA hypermethylation of its promoter (12.5%). Silencing and ectopic expression of CAMK2N1 respectively enhanced and suppressed cell proliferation, colony formation, and xenograft tumor growth in nude mice. Comparative proteomics revealed that CAMK2N1 silencing transcriptionally deregulated the genes regulated by E2F1 (89 out of the 114 E2F-signaling targets, P = 8.8E-240). The promoter assays revealed that CAMK2N1 suppressed E2F1-mediated transcriptional activities. CAMK2N1 silencing induced cyclins D/E expression, whereas its ectopic expression induced P27/KIP1 expression and suppressed the cell cycle. CAMK2N1 was translocated from the nuclei to the cytoplasm when cell proliferation reached the stationary phase, where its functions as an endogenous inhibitor of CAMK2. In conclusion, CAMK2NA is a novel 1p36 tumor suppressor gene that inhibits E2F1 transcriptional activities and induces P27/KIP1 expression. CAMK2N1-CAMK2 signaling forms a mechanism that restricts the cell cycle progression. Its deregulation could lead to tumorigenesis and might serve as promising therapeutic targets. Highlights: Cell-cycle checkpoints primarily tether cell proliferation. Human kinome/phosphatome screening identified CAMK2N1 is a tumor suppressor of HCC. Genome deletion and promoter methylation of CAMK2N1 facilitate HCC development. CAMK2N1 suppresses E2F1 and induces P27/KIP to restrict the cell cycle at G1/S and G2/M. CAMK2N1 regulates cell cycle progression by its subcellular trafficking.