Roles of CCNB2 and NKX3-1 in Nasopharyngeal Carcinoma.

Background: Nasopharyngeal carcinoma (NPC) is leading form of cancer occurring in a few well-defined regions, including southern China. NPC possess a unique and intricate etiology that remains to be elucidated. Herein, we determine expression patterns of CCNB2 and NKX3-1 and identify their roles in NPC. Materials and Methods: Gene-expression profiles of NPC in the Gene Expression Omnibus (GEO) were analyzed. Cell viability, invasion, apoptosis, cell cycle entry and mitochondrial membrane potential (MMP) were evaluated in the presence of NKX3-1 or in the absence of CCNB2. Results: In all, 187 upregulated genes and 683 downregulated genes were obtained by analyzing GSE13597. NKX3-1, the downregulated gene, and CCNB2, the upregulated one, were further confirmed by in vitro studies. Overexpression of NKX3-1 was shown to inhibit NPC cell viability and invasion. Knockdown of CCNB2 was demonstrated to reduce cell cycle entry and MMP but induce apoptosis in NPC cells. Conclusions: Taken together, the key finding obtained from the study supports CCNB2 and NKX3-1 as two promising therapeutic candidates for NPC. Molecular mechanisms that control CCNB2 or NKX3-1 disturbance require further investigation and clarification.

Light acts on the zebrafish circadian clock to suppress rhythmic mitosis and cell proliferation.

A fundamental role of the circadian clock is to control biochemical and physiological processes such that they occur an optimal time of day. One of the most significant clock outputs from a clinical as well as basic biological standpoint is the timing of the cell cycle. Here we show that the circadian clock regulates the timing of mitosis in a light-responsive, clock-containing zebrafish cell line. Disrupting clock function, using a CLOCK1 dominant-negative construct or constant light, blocks the gating of cell division, demonstrating that this mitotic rhythm is cell autonomous and under control of the circadian pacemaker. Quantitative PCR reveals that several key mitotic genes, including Cyclin B1, Cyclin B2, and cdc2, are rhythmically expressed and clock-controlled. Peak expression of these genes occurs at a critical phase required to gate mitosis to the late night/early morning. Using clock and cell cycle luminescent reporter zebrafish cell lines, we show that light strongly represses not only circadian clock function, but also mitotic gene expression, and consequently slows cell proliferation.

Regulation of cyclin B2 expression and cell cycle G2/m transition by menin.

Multiple endocrine neoplasia type 1 (MEN1) results from mutations in tumor suppressor gene Men1, which encodes nuclear protein menin. Menin up-regulates certain cyclin-dependent kinase inhibitors through increasing histone H3 lysine 4 (H3K4) methylation and inhibits G(0)/G(1) to S phase transition. However, little is known as to whether menin controls G(2)/M-phase transition, another important cell cycle checkpoint. Here, we show that menin expression delays G(2)/M phase transition and reduces expression of Ccnb2 (encoding cyclin B2). Menin associates with the promoter of Ccnb2 and reduces histone H3 acetylation, a positive chromatin marker for gene transcription, at the Ccnb2 locus. Moreover, Men1 ablation leads to an increase in cyclin B2 expression, histone H3 acetylation at the Ccnb2 locus, and G(2)/M transition. In contrast, knockdown of cyclin B2 diminishes the number of cells at M phase and reduces cell proliferation. Furthermore, menin interferes with binding of certain positive transcriptional regulators, such as nuclear factor Y (NF-Y), E2 factors (E2Fs), and histone acetyltransferase CREB (cAMP-response element-binding protein)-binding protein (CBP) to the Ccnb2 locus. Notably, MEN1 disease-related mutations, A242V and L22R, abrogate the ability of menin to repress cyclin B2 expression and G(2)/M transition. Both of the mutants fail to reduce the acetylated level of the Ccnb2 locus. Together, these results suggest that menin-mediated repression of cyclin B2 is crucial for inhibiting G(2)/M transition and cell proliferation through a previously unrecognized molecular mechanism for menin-induced suppression of MEN1 tumorigenesis.