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UTX/KDM6A encodes a major histone H3 lysine 27 (H3K27) demethylase, and is frequently mutated in various types of human cancers. Although UTX appears to play a crucial role in oncogenesis, the mechanisms involved are still largely unknown. Here we show that a specific pharmacological inhibitor of H3K27 demethylases, GSK-J4, induces the expression of transcription activating factor 4 (ATF4) protein as well as the ATF4 target genes (e.g. PCK2, CHOP, REDD1, CHAC1 and TRIB3). ATF4 induction by GSK-J4 was due to neither transcriptional nor post-translational regulation. In support of this view, the ATF4 induction was almost exclusively dependent on the heme-regulated eIF2α kinase (HRI) in mouse embryonic fibroblasts (MEFs). Gene expression profiles with UTX disruption by CRISPR-Cas9 editing and the following stable re-expression of UTX showed that UTX specifically suppresses the expression of the ATF4 target genes, suggesting that UTX inhibition is at least partially responsible for the ATF4 induction. Apoptosis induction by GSK-J4 was partially and cell-type specifically correlated with the activation of ATF4-CHOP. These findings highlight that the anti-cancer drug candidate GSK-J4 strongly induces ATF4 and its target genes via HRI activation and raise a possibility that UTX might modulate cancer formation by regulating the HRI-ATF4 axis. [ABSTRACT FROM AUTHOR]

Summary: Oral squamous cell carcinoma (OSCC) is the most frequent malignant neoplasm of the head and neck region. Conversion of normal cells to cancer cells is achieved through a multi-step process that is closely associated with the accumulation of multiple gene changes including both oncogenes and tumour suppressor genes. The proliferation and progression of cancer may be caused by abnormalities of various positive and negative cell cycle regulators. Cell cycle progression is positively regulated by multiple cyclins and cyclin-dependent kinases (Cdks) and cyclin/Cdk complexes are negatively regulated by a number of Cdk inhibitors including p27. p27 is a Cdk inhibitor and plays an important role in negative regulation of the cell cycle during G0 and G1 phases. Degradation of p27 is a critical event for the G1/S transition and occurs through ubiquitination by SCFSkp2 and subsequent degradation by the 26S proteasome. It has been revealed that down-regulation of p27 is frequently found in various cancers, including OSCC, and is due to an enhancement of its degradation. Importantly, down-regulation of p27 is well associated with its malignancy including poor prognosis in various cancers. Moreover, aggressive human cancers express low levels of p27 because of its decreased stability. More recent evidence suggests that Skp2 and Cks1, the specific recognition factors for p27 ubiquitination, have oncogenic properties. This review will focus on down-regulation of p27 and mechanism of its down-regulation in OSCC. [Copyright &y& Elsevier]

Objective: It is well known that reduction of the cyclin-dependent kinase inhibitor p27[sup Kip1] protein correlates with the malignant behavior of various cancers including oral squamous cell carcinoma (OSCC). The loss of p27[sup Kip1] protein is suggested to be due to the enhancement of its posttranslational degradation. In the present study, to evaluate the effects of p27[sup Kip1] transfection on the cell cycle, we transfected OSCC cell lines with a high activity of p27[sup Kip1] degradation with p27[sup Kip1] threonine 187-to-alanine (T187A) mutant gene, which is not influenced by ubiquitin-mediated degradation, as well as with wild type gene. Methods: We transfected p27[sup Kip1] T187A mutant and wild type gene into OSCC cell lines (HSC2 and HSC3) by using an ecdysone-inducible gene expression system. Results: After treatment with ponasterone A, we could find an induction of both p27[sup Kip1] wild type and T187A mutant protein. Both wild type and T187A mutant protein induced by 5 μM ponasterone A inhibited cell growth and increased cell number at the G1 phase. After treatment with 1 μM ponasterone A, ectopic p27[sup Kip1] protein was degraded in wild type clones, but not in T187A mutant clones. Moreover, transfection of the T187A mutant gene was more effective in inhibiting cell growth even by induction of a small amount of protein. Conclusion: We suggest that the transfection of the p27[sup Kip1] T187A mutant gene can be a modality of cancer gene therapy for OSCC.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The chromosome passenger complex (CPC) is a kinase complex formed by Aurora B, borealin, survivin and inner centromere protein (INCENP). The CPC is active during mitosis and contributes to proper chromosome segregation via the phosphorylation of various substrates. Overexpression of each CPC component has been reported in most cancers. However, its significance remains unclear, as only survivin is known to confer chemoresistance. This study showed that the overexpression of borealin, a CPC component, stabilized survivin protein depending on its interaction with survivin. Unexpectedly, the accumulation of survivin by borealin overexpression did not affect the well-characterized functions of survivin, such as chemoresistance and cell proliferation. Interestingly, the overexpression of borealin promoted lactate production but not the overexpression of the deletion mutant that lacks the ability to bind to survivin. Consistent with these findings, the expression levels of glycolysis-related genes were enhanced in borealin-overexpressing cancer cells. Meanwhile, the overexpression of survivin alone did not promote lactate production. Overall, the accumulation of the borealin–survivin complex promoted glycolysis in squamous cell carcinoma cells. This mechanism may contribute to cancer progression via excessive lactate production. • Borealin stabilizes survivin protein depending on its binding to survivin. • Borealin-mediated survivin accumulation does not affect antiapoptotic function. • Borealin-survivin complex promotes glycolysis. [ABSTRACT FROM AUTHOR]

Cancer recurrence due to tumor cell quiescence after therapy and long-term remission is associated with cancer-related death. Previous studies have used cell models that are unable to return to a proliferative state; thus, the transition between quiescent and proliferative states is not well understood. Here, we report monolayer cancer cell models wherein the human non-small cell lung carcinoma cell line H2228 and pancreatic cancer cell line AsPC-1 can be reversibly induced to a quiescent state under hypoxic and serum-starved (HSS) conditions. Transcriptome and metabolome dual-omics profiles of these cells were compared with those of the human lung adenocarcinoma cell line A549, which was unable to enter a quiescent state under HSS conditions. The quiescence-inducible cells had substantially lower intracellular pyruvate and ATP levels in the quiescent state than in the proliferative state, and their response to sudden demand for energy was dramatically reduced. Furthermore, in quiescence-inducible cells, the transition between quiescent and proliferative states of these cells was regulated by the balance between the proliferation-promoting Ras and Rap1 signaling and the suppressive AGE/RAGE signaling. These cell models elucidate the transition between quiescent and proliferative states, allowing the development of drug-screening systems for quiescent tumor cells. [ABSTRACT FROM AUTHOR]

Aurora kinases are known to play a key role in maintaining mitotic fidelity, and overexpression of aurora kinases has been noted in various tumors. Overexpression of aurora kinase activity is thought to promote cancer development through a loss of centrosome or chromosome number integrity. Here we observed augmentation of G12V-mutated HRAS-induced neoplastic transformation in BALB/c 3T3 A31-1-1 cells transfected with Aurora-A. Aurora-A-short hairpin RNA (shRNA) experiments showed that the expression level of Aurora-A determines susceptibility to transformation. Aurora-A gene amplification was noted in human patients with tongue or gingival squamous carcinoma (4/11). Amplification was observed even in pathologically normal epithelial tissue taken at sites distant from the tumors in two patients with tongue cancer. However, overexpression of Aurora-A mRNA was observed only within the tumors of all patients examined (11/11). Our data indicate that Aurora-A gene amplification and overexpression play a role in human carcinogenesis, largely due to the effect of Aurora-A on oncogenic cell growth, rather than a loss of maintenance of centrosomal or chromosomal integrity.Oncogene (2005) 24, 1122-1127. doi:10.1038/sj.onc.1208293 Published online 13 December 2004 [ABSTRACT FROM AUTHOR]

Background: Spindle cell squamous carcinoma (SCSC) is a rare and peculiar biphasic malignant neoplasm that occurs mainly in the upper aerodigestive tract. It consists of sarcomatoid proliferation of pleomorphic spindle-shaped cells and squamous cell carcinoma. Methods: Here, we established a SCSC cell line from a tumour arisen in gingiva. We characterized the feature of a SCSC cell line by immunohistochemistry. To know the biological feature, we examined the cell growth, invasiveness and epithelial-mesenchymal transition markers of a SCSC cell line in comparison with oral squamous cell carcinoma (OSCC) cell lines. Results: By immunohistochemical analyses, the primary tumour expressed cytokeratin and vimentin, indicating carcinosarcoma-like characters. This tumour also showed overexpression of p53 protein. Cultured SCSC cells resulted in bypass of crisis and maintenance over passage 100. The established SCSC cell line was spindle-shaped and showed identical immunohistochemical characters to those of primary tumour cells. Similar to the primary tumour, the cell line showed p53 overexpression and had p53 mutation at codon 132: AAG (lys)→AAT (asp). The SCSC cell line grew slower than two other OSCC cell lines (MSCC-1 and HSC-2), whereas SCSC cells had remarkable invasiveness in comparison with these cell lines. Moreover, SCSC cells expressed wnt-5a and vimentin mRNA at high levels, but did not express E-cadherin mRNA. This expression pattern of the markers was similar to that of mesenchymal cells, not of epithelial cells. Conclusion: In the present study, we newly established a SCSC cell line with strong invasiveness. This is the first report on the establishment of SCSC cell line. The SCSC cell line can be a useful cell model for the study to know the cytodifferentiation and nature of SCSC. [ABSTRACT FROM AUTHOR]

Aurora-B, previously known as AIM-1, is a conserved eukaryotic mitotic protein kinase. In mammals, this kinase plays an essential role in chromosomal segregation processes, including chromosome condensation, alignment, control of spindle checkpoints, chromosome segregation, and cytokinesis. Aurora-B is overexpressed in various cancer cells, suggesting that the kinase activity perturbs chromosomal segregation processes. Its forced overexpression induces chromosomal number instability and progressive tumorigenicity in rodent cells in vitro and in vivo. Nevertheless, based on focus formation in BALB/c 3T3 A31-1-1 cells, Aurora-B is not oncogenic. Here, we show that Aurora-B kinase activity augments Ras-mediated cell transformation. RNA interference with short hairpin RNA inhibits transformation by Ras and its upstream oncogene Src, but not by the downstream oncogene Raf. In addition, the inner centromere protein, which is a passenger protein associated with Aurora-B, has a similar ability to potentiate the activity of oncogenic Ras. These data indicate that elevated Aurora-B activity promotes transformation by oncogenic Ras by enhancing oncogenic signaling and by converting chromosome number-stable cells to aneuploid cells.Oncogene (2005) 24, 7266–7272. doi:10.1038/sj.onc.1208884; published online 18 July 2005 [ABSTRACT FROM AUTHOR]