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.

人类kinome /磷原子筛查确定了抑制人类肝细胞癌（HCC）发展的CAMK2N1基因。在47％的HCC中发现CAMK2N1下调与预后不良有关。下调主要归因于其基因组缺失（28.4％）和其启动子的DNA超甲基化（12.5％）。沉默和异位表达的CAMK2N1分别增强和抑制裸鼠的细胞增殖，集落形成和异种移植肿瘤的生长。比较蛋白质组学显示，CAMK2N1沉默使E2F1调控的基因转录失调（在114个E2F信号转导靶标中，有89个P = 8.8E-240）。启动子分析表明，CAMK2N1抑制了E2F1介导的转录活性。CAMK2N1沉默诱导细胞周期蛋白D / E表达，而其异位表达诱导P27 / KIP1表达并抑制细胞周期。当细胞增殖达到固定相时，CAMK2N1从细胞核转移到细胞质，在固定相中它作为CAMK2的内源性抑制剂起作用。总之，CAMK2NA是一种新型的1p36抑癌基因，可抑制E2F1转录活性并诱导P27 / KIP1表达。CAMK2N1-CAMK2信号传导形成限制细胞周期进程的机制。它的失调可能导致肿瘤发生，并可能成为有希望的治疗靶标。