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Clear cell renal cell carcinoma (ccRCC) is a common genitourinary malignancy characterized by dysregulated cellular metabolism leading to aberrant glucose metabolism, fatty acid accumulation, and excessive reactive oxygen species production. ccRCC cells exhibit an augmented oxidative stress response. Complex interactions between iron metabolism and lipid homeostasis in ccRCC cells require a counteracting response that enables ferroptosis evasion and survival maintenance. Additionally, abnormal GA-binding protein transcription factor subunit alpha (GABPA) expression is associated with ccRCC occurrence and development, but its impact on ferroptosis-related molecular mechanisms remains unclear. Herein, we examined the impact of the GABPA-ACSL4 pathway on ferroptosis in ccRCC through bioinformatics analysis, as well as in vitro and in vivo experiments. In contrast to that in adjacent normal tissues, GABPA expression was significantly downregulated in ccRCC tissues, and this downregulation was linked to poor overall survival. Increased GABPA expression suppressed ccRCC cell proliferation, migration, and invasion. Moreover, GABPA overexpression increased the susceptibility of ccRCC cells to ferroptosis. Additionally, GABPA directly bound to the promoter region of ACSL4, promoting ferroptosis. Thus, inducing the GABPA-ACSL4 pathway activates ferroptosis, inhibits proliferation or metastasis, and exerts anticancer activity in ccRCC. These findings have important implications for regulating ccRCC occurrence and development., (© 2024. The Author(s).)

Background: Thermogenic beige adipocytes, which dissipate energy as heat, are found in neonates and adults. Recent studies show that neonatal beige adipocytes are highly plastic and contribute to >50% of beige adipocytes in adults. Neonatal beige adipocytes are distinct from recruited beige adipocytes in that they develop independently of temperature and sympathetic innervation through poorly defined mechanisms., Methods: We characterized the neonatal beige adipocytes in the inguinal white adipose tissue (iWAT) of C57BL6 postnatal day 3 and 20 mice (P3 and P20) by imaging, genome-wide RNA-seq analysis, ChIP-seq analysis, qRT-PCR validation, and biochemical assays., Results: We found an increase in acetylated histone 3 lysine 27 (H3K27ac) on the promoter and enhancer regions of beige-specific gene UCP1 in iWAT of P20 mice. Furthermore, H3K27ac ChIP-seq analysis in the iWAT of P3 and P20 mice revealed strong H3K27ac signals at beige adipocyte-associated genes in the iWAT of P20 mice. The integration of H3K27ac ChIP-seq and RNA-seq analysis in the iWAT of P20 mice reveal epigenetically active signatures of beige adipocytes, including oxidative phosphorylation and mitochondrial metabolism. We identify the enrichment of GA-binding protein alpha (GABPα) binding regions in the epigenetically active chromatin regions of the P20 iWAT, particularly on beige genes, and demonstrate that GABPα is required for beige adipocyte differentiation. Moreover, transcriptomic analysis and glucose oxidation assays revealed increased glycolytic activity in the neonatal iWAT from P20., Conclusions: Our findings demonstrate that epigenetic mechanisms regulate the development of peri-weaning beige adipocytes via GABPα. Further studies to better understand the upstream mechanisms that regulate epigenetic activation of GABPα and characterization of the metabolic identity of neonatal beige adipocytes will help us harness their therapeutic potential in metabolic diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mooli, Zhu, Khan, Nagati, Michealraj, Jurczak and Ramakrishnan.)

The transcriptional de-repression of the telomerase reverse transcriptase (TERT) gene and subsequent activation of telomerase is a prerequisite step in malignant transformation and progression. Recently, the gain-of-function mutation of the TERT promoter was identified in many types of human malignancies, and the mutated promoter acquires de novo ETS binding motifs through which the TERT transcription is activated. The ETS family transcription factors GABPA and GABPB1 have been shown to act as master drivers for the mutant TERT promoter activity. Indeed, GABPA or GABPB1 depletion leads to the down-regulation of TERT expression in the mutant TERT promoter-bearing cancer cells, and is thus proposed as targets for cancer therapy. Surprisingly, however, despite its key role in activating the mutant TERT promoter and telomerase, GABPA may itself function as a potent tumor suppressor in several malignancies. In this review, we address the collaboration between GABPA and mutant TERT promoter in cancer development, discuss selection trade-offs among different activities of GABPA in cancer evolution, and underscore the suppressive function of GABPA in cancer progression and implications in precision oncology., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Mitotic bookmarking constitutes a mechanism for transmitting transcriptional patterns through cell division. Bookmarking factors, comprising a subset of transcription factors (TFs), and multiple histone modifications retained in mitotic chromatin facilitate reactivation of transcription in the early G1 phase. However, the specific TFs that act as bookmarking factors remain largely unknown. Previously, we identified the "early G1 genes" and screened TFs that were predicted to bind to the upstream region of these genes, then identified GA-binding protein transcription factor alpha subunit (GABPA) and Sp1 transcription factor (SP1) as candidate bookmarking factors. Here we show that GABPA and multiple histone acetylation marks such as H3K9/14AC, H3K27AC, and H4K5AC are maintained at specific genomic sites in mitosis. During the M/G1 transition, the levels of these histone acetylations at the upstream regions of genes bound by GABPA in mitosis are decreased. Upon depletion of GABPA, levels of histone acetylation, especially H4K5AC, at several gene regions are increased, along with transcriptional induction at 1 h after release. Therefore, we proposed that GABPA cooperates with the states of histone acetylation to act as a novel bookmarking factor which, may negatively regulate transcription during the early G1 phase.

Background: Increasing evidence indicates that abnormal expression of GABPA is associated with tumor development and progression. However, the function and clinicopathological significance of GABPA in hepatocellular carcinoma (HCC) remain obscure., Methods: The mRNA and protein expression of GABPA in HCC clinical specimens and cell lines was examined by real-time PCR and western blotting, respectively. Follow-up data were used to uncover the relationship between GABPA expression and the prognosis of HCC patients. HCC cell lines stably overexpressing or silencing GABPA were established to explore the function of GABPA in HCC cell migration and invasion by Transwell and wound healing assays in vitro and in a xenograft model in vivo. Restoration of function analysis was used to examine the underlying molecular mechanisms., Results: GABPA was downregulated at the protein and mRNA levels in HCC tissues compared with adjacent normal tissues. Decreased GABPA expression was correlated with alpha-fetoprotein levels (P = 0.001), tumor grade (P = 0.017), and distant metastasis (P = 0.021). Kaplan-Meier survival analysis showed that patients with lower GABPA expression had significantly shorter survival times than those with higher GABPA (P = 0.031). In vivo and in vitro assays demonstrated that GABPA negatively regulated HCC cell migration and invasion, and the effect of GABPA on HCC cell migration was mediated at least partly by the regulation of E-cadherin., Conclusions: Collectively, our data indicate that GABPA inhibits HCC cell migration by modulating E-cadherin and could serve as a novel biomarker for HCC prognosis. GABPA may act as a tumor suppressor during HCC progression and metastasis, and is a potential therapeutic target in HCC.