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Background: Dysregulation of long non-coding RNAs (lncRNAs) is an important component of tumorigenesis. Aberrant expression of lncRNA taurine upregulated gene 1 (lncTUG1) has been reported in various tumors; however, its precise role and key targets critically involved in osteosarcoma (OS) progression remain unclear. Methods: The expression profiles of lncRNAs and their regulated miRNAs related to OS progression were assessed by bioinformatics analysis and confirmed by qRT-PCR of OS cells. The miRNA targets were identified by transcriptome sequencing and verified by luciferase reporter and RNA pull-down assays. Several in vivo and in vitro approaches, including CCK8 assay, western blot, qRT-PCR, lentiviral transduction and OS cell xenograft mouse model were established to validate the effects of lncTUG1 regulation of miRNA and the downstream target genes on OS cell growth, apoptosis and progression. Results: We found that lncTUG1 and miR-26a-5p were inversely up or down-regulated in OS cells, and siRNA-mediated lncTUG1 knockdown reversed the miR-26a-5p down-regulation and suppressed proliferation and enhanced apoptosis of OS cells. Further, we identified that an oncoprotein ZBTB7C was also upregulated in OS cells that were subjected to lncTUG1/miR-26a-5p regulation. More importantly, ZBTB7C knockdown reduced the ZBTB7C upregulation and ZBTB7C overexpression diminished the anti-OS effects of lncTUG1 knockdown in the OS xenograft model. Conclusions: Our data suggest that lncTUG1 acts as a miR-26a-5p sponge and promotes OS progression via up-regulating ZBTB7C, and targeting lncTUG1 might be an effective strategy to treat OS.

Background: Dysregulation of long non-coding RNAs (lncRNAs) is an important component of tumorigenesis. Aberrant expression of lncRNA taurine upregulated gene 1 (lncTUG1) has been reported in various tumors; however, its precise role and key targets critically involved in osteosarcoma (OS) progression remain unclear., Methods: The expression profiles of lncRNAs and their regulated miRNAs related to OS progression were assessed by bioinformatics analysis and confirmed by qRT-PCR of OS cells. The miRNA targets were identified by transcriptome sequencing and verified by luciferase reporter and RNA pull-down assays. Several in vivo and in vitro approaches, including CCK8 assay, western blot, qRT-PCR, lentiviral transduction and OS cell xenograft mouse model were established to validate the effects of lncTUG1 regulation of miRNA and the downstream target genes on OS cell growth, apoptosis and progression., Results: We found that lncTUG1 and miR-26a-5p were inversely up or down-regulated in OS cells, and siRNA-mediated lncTUG1 knockdown reversed the miR-26a-5p down-regulation and suppressed proliferation and enhanced apoptosis of OS cells. Further, we identified that an oncoprotein ZBTB7C was also upregulated in OS cells that were subjected to lncTUG1/miR-26a-5p regulation. More importantly, ZBTB7C knockdown reduced the ZBTB7C upregulation and ZBTB7C overexpression diminished the anti-OS effects of lncTUG1 knockdown in the OS xenograft model., Conclusions: Our data suggest that lncTUG1 acts as a miR-26a-5p sponge and promotes OS progression via up-regulating ZBTB7C, and targeting lncTUG1 might be an effective strategy to treat OS., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (© 2023 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

Gluconeogenesis is essential for blood glucose homeostasis during fasting and is regulated by various enzymes, which are encoded by gluconeogenic genes. Those genes are controlled by various transcription factors. Zinc finger and BTB domain–containing 7c (Zbtb7c, also called Kr-pok) is a BTB-POZ family transcription factor with proto-oncogenic activity. Previous findings have indicated that Zbtb7c is involved in the regulation of fatty acid biosynthesis, suggesting an involvement also in primary metabolism. We found here that fasting induced Zbtb7c expression in the mouse liver and in primary liver hepatocytes. We also observed that Zbtb7c-knockout mice have decreased blood glucose levels, so we investigated whether Zbtb7c plays a role in gluconeogenesis. Indeed, differential gene expression analysis of Zbtb7c-knockout versus wild type mouse livers showed downregulated transcription of gluconeogenic genes encoding the glucose 6-phosphatase catalytic subunit (G6pc) and phosphoenolpyruvate carboxykinase 1 (Pck1), while Zbtb7c expression upregulated these two genes, under fasting conditions. Mechanistically, we found that when complexed with histone deacetylase 3 (Hdac3), Zbtb7c binds insulin response elements (IREs) within the G6pc and Pck1 promoters. Moreover, complexed Zbtb7c deacetylated forkhead box O1 (Foxo1), thereby increasing Foxo1 binding to the G6pc and Pck1 IREs, resulting in their transcriptional activation. These results demonstrate Zbtb7c to be a crucial metabolic regulator of blood glucose homeostasis, during mammalian fasting. • Zbtb7c is induced and plays a critical role in gluconeogenesis by activating G6pc and Pck1 gene transcription during mice fasting. • Zbtb7c complexed with Hdac3, and deacetylated Foxo1, which increases DNA binding of Foxo1. • Zbtb7c is critical in increasing Foxo1 binding to the IREs. [ABSTRACT FROM AUTHOR]

As an important transcription factor, zinc-finger and BTB domain-containing 7B (ZBTB7C) plays an important role in a variety of tumors. However, its relationship with human immunity is unclear. This article aims to study its differential expression and survival across cancers and explore the relationships between its differential expression and the tumor microenvironment and immune cell infiltration. In this study, we used R software to process The Cancer Genome Atlas (TCGA) data and explored the expression pattern and prognostic value of ZBTB7C across cancers. Next, we comprehensively explained the important role of ZBTB7C in several tumor types in terms of tumor mutational burden (TMB), microsatellite instability (MSI) and immune cell infiltration. In general, the expression level of ZBTB7C in tumor tissues was lower than that in normal tissues. Highly expressed ZBTB7C was beneficial to the survival of patients with colon adenocarcinoma (COAD), lymphoid neoplasm diffuses large B cell lymphoma (DLBC), esophageal carcinoma (ESCA) and mesothelioma (MESO). Multivariate analysis showed that the expression of ZBTB7C was an independent prognostic factor in COAD and MESO. In COAD, the expression of ZBTB7C was positively correlated with both TMB and MSI. In colorectal cancer (CRC), there was a significant positive correlation between ZBTB7C expression and immune cell infiltration, especially the infiltration of mast cells and B cells. In conclusion, ZBTB7C can be used as a potential therapeutic target across cancers and is related to immune cell infiltration.

Currently, colorectal cancer (CRC) predictions are based on an early diagnosis and the tumor-node-metastasis (TNM) stage, but the outcomes of patients with the same cancer type are difficult to predict. Novel molecular tests for the early diagnosis and stratification of CRC patients must be devised. After our initial bioinformatics screen, we examined zinc finger and BTB domain-containing 7C (ZBTB7C). To date, few studies have investigated ZBTB7C in CRC, necessitating further analyses of its expression and regulatory mechanism in CRC. ZBTB7C mRNA and protein expression was detected in CRC and corresponding non-CRC tissues. We evaluated the relationship between clinical prognosis and ZBTB7C protein levels using Cox regression analysis and Kaplan-Meier curves. A receiver operating characteristic (ROC) curve was generated to verify the diagnostic performance of ZBTB7C levels in CRC. Several bioinformatics techniques were applied to analyze the potential molecular mechanism of ZBTB7C. Low mRNA and protein levels of ZBTB7C were detected in tumor tissues from CRC patients. The survival curve predicted a poor prognosis for CRC patients exhibiting low ZBTB7C expression (P=0.001). According to the univariate Cox regression analysis, older age, a high TNM stage and low ZBTB7C expression were responsible for poor outcomes in CRC patients. The multivariate analysis further revealed ZBTB7C as an independent prognostic factor for CRC (P=0.015). The area under the curve of ZBTB7C expression for CRC diagnosis was 0.970 (95% confidence interval, 0.9447-0.9946; P < 0.0001). According to in silico analyses, genes coexpressed with ZBTB7C are associated mainly with the Ras and Wnt signaling pathways. Overall, ZBTB7C is downregulated in CRC and represents an early diagnostic marker and independent prognostic factor for CRC. ZBTB7C may be functionally mediated by different pathways or targeting miRNAs., Competing Interests: None., (AJTR Copyright © 2020.)

Gluconeogenesis is essential for blood glucose homeostasis during fasting and is regulated by various enzymes, which are encoded by gluconeogenic genes. Those genes are controlled by various transcription factors. Zinc finger and BTB domain-containing 7c (Zbtb7c, also called Kr-pok) is a BTB-POZ family transcription factor with proto-oncogenic activity. Previous findings have indicated that Zbtb7c is involved in the regulation of fatty acid biosynthesis, suggesting an involvement also in primary metabolism. We found here that fasting induced Zbtb7c expression in the mouse liver and in primary liver hepatocytes. We also observed that Zbtb7c-knockout mice have decreased blood glucose levels, so we investigated whether Zbtb7c plays a role in gluconeogenesis. Indeed, differential gene expression analysis of Zbtb7c-knockout versus wild type mouse livers showed downregulated transcription of gluconeogenic genes encoding the glucose 6-phosphatase catalytic subunit (G6pc) and phosphoenolpyruvate carboxykinase 1 (Pck1), while Zbtb7c expression upregulated these two genes, under fasting conditions. Mechanistically, we found that when complexed with histone deacetylase 3 (Hdac3), Zbtb7c binds insulin response elements (IREs) within the G6pc and Pck1 promoters. Moreover, complexed Zbtb7c deacetylated forkhead box O1 (Foxo1), thereby increasing Foxo1 binding to the G6pc and Pck1 IREs, resulting in their transcriptional activation. These results demonstrate Zbtb7c to be a crucial metabolic regulator of blood glucose homeostasis, during mammalian fasting., (Copyright © 2019 Elsevier B.V. All rights reserved.)