The ARF and INK4a genes are located on the same CDKN2a locus, both showing its tumor-suppressive activity. ARF has been shown to monitor potentially harmful oncogenic signalings, making incipient cancer cells undergo senescence or programmed cell death to prevent cancer. On the other hand, INK4a detects both aging and incipient cancer cell signals. The efficiency of detection of oncogenic signals is more efficient for the for the former than the latter in the mouse system. Both ARF and INK4a genes are inactivated by gene deletion, promoter methylation, frameshift, aberrant splicing although point mutations for the coding region affect only the latter. Recent studies show the splicing alterations that affect only ARF or both ARF and INK4a genes, suggesting that ARF is inactivated in human tumors more frequently than what was previously thought. The ARF gene is activated by E2Fs and Dmp1 transcription factors while it is repressed by Bmi1, Tbx2/3, Twist1, and Pokemon nuclear proteins. It is also regulated at protein levels by Arf ubiquitin ligase named ULF, MKRN1, and Siva1. The prognostic value of ARF overexpression is controversial since it is induced in early-stage cancer cells to eliminate premalignant cells (better prognosis); however, it may also indicate that the tumor cells have mutant p53 associated with worse prognosis. The ARF tumor suppressive protein can be used as a biomarker to detect early-stage cancer cells as well as advanced stage tumors with p53 inactivation.

Introduction: Cancer is one of the serious health problems in worldwide. For the development of radical cancer treatment, cancer stem cells (CSCs) are getting an issue of focus. CSCs are thought to be resistant to chemotherapy and cause metastasis. Although it is very important to understand their characters in detail, the knowledge so far is not sufficient due to their low ratio in tumor tissues. Subjects and Methods: We have induced CSCs from induced pluripotent stem cells (iPSCs) culturing in the conditioned media from cancer-derived cells without introducing genes or mutations. These induced CSCs actually have CSCs-like properties of self-renewal, differentiation potential, and tumorigenicity. In this study, their gene expression data are compared with more than 1000 sets of data from normal stem cells, our CSCs, CSCs obtained from cancer tissues or cell lines and cancer cells, which obtained from Gene Expression Omnibus. Results: Although there were no known cancer stem cell markers which can distinguish CSCs from other cell types, clustering with spherical self-organizing map revealed the expression of NTNG1, ABLIM2, DNM3, EDN1, XLOC_001990, and ISY1-RAB43 are significantly high in CSCs. Conclusion: Their expression should help to find CSCs as the markers in the future. Simultaneously, the function of these genes should become important to be clarified.

Context/Aims: Metabolic reprogramming and cellular plasticity drive tumorigenesis. However, how these cellular events collectively contribute to the oncogenic process is poorly understood. Epithelial-mesenchymal transition (EMT), a fundamental mechanism of cellular plasticity, is governed by the EMT transcription repressors such as Snail. In the present study, through establishment and characterization of inducible overexpression of Snail in A549 lung cancer cells, we aim to define the metabolic reprogramming in response to Snail in the EMT of lung cancer cells. Methods/Results: Our metabolomic analysis suggests that forced expression of Snail accompanied reduced diversion of glycolytic metabolites to the serine/glycine metabolic shunt, a critical metabolic branch that distributes glucose catabolic intermediates to the major anabolic pathways. Our gene expression profiling and molecular characterization revealed that Snail actively suppressed the expression of glycine decarboxylase (GLDC), a key enzyme on the serine/glycine metabolic shunt, through binding to an evolutionarily conserved E-box motif and thereby inhibiting the promoter of the GLDC gene. Besides, knockdown of GLDC led to a cellular function shift from proliferation to migration. Conclusion: This study has revealed a novel molecular link that integrates the serine/glycine metabolism with the Snail-mediated EMT program in cancer cells.