bims-meprid 2022-11-06 papers

Issue of 2022‒11‒06
two papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

Cancer Res. 2022 Nov 01. pii: CAN-22-1029. [Epub ahead of print]

Mitochondrial uncoupling induces epigenome remodeling and promotes differentiation in neuroblastoma.

Haowen Jiang, Rachel L Greathouse, Sarah Jane Tiche, Man Zhao, Bo He, Yang Li, Albert M Li, Balint Forgo, Michaela Yip, Allison Li, Moriah Shih, Selene Banuelos, Meng-Ning Zhou, Joshua J Gruber, Erinn B Rankin, Zhen Hu, Hiroyuki Shimada, Bill Chiu, Jiangbin Ye.

The Warburg effect is the major metabolic hallmark of cancer. According to Warburg himself, the consequence of the Warburg effect is cell dedifferentiation. Therefore, reversing the Warburg effect might be an approach to restore cell differentiation in cancer. In this study, we used a mitochondrial uncoupler, niclosamide ethanolamine (NEN), to activate mitochondrial respiration, which induced neural differentiation in neuroblastoma cells. NEN treatment increased the nicotinamide adenine dinucleotide (NAD)+/NADH and pyruvate/lactate ratios and also the α-ketoglutarate (α-KG)/2- hydroxyglutarate (2-HG) ratio. Consequently, NEN treatment induced promoter CpG island demethylation and epigenetic landscape remodeling, activating the neural differentiation program. In addition, NEN treatment upregulated p53 but downregulated N-Myc and β-catenin signaling in neuroblastoma cells. Importantly, even under hypoxia, NEN treatment remained effective in inhibiting 2-HG generation, promoting DNA demethylation, and suppressing hypoxia-inducible factor signaling. Dietary NEN intervention reduced tumor growth rate, 2-HG levels, and expression of N-Myc and β-catenin in tumors in an orthotopic neuroblastoma mouse model. Integrative analysis indicated that NEN treatment upregulated favorable prognosis genes and downregulated unfavorable prognosis genes, which were defined using multiple neuroblastoma patient datasets. Altogether, these results suggest that mitochondrial uncoupling is an effective metabolic and epigenetic therapy for reversing the Warburg effect and inducing differentiation in neuroblastoma.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-1029

Cell Rep. 2022 Nov 01. pii: S2211-1247(22)01429-2. [Epub ahead of print]41(5): 111568

Metabolic regulation by p53 prevents R-loop-associated genomic instability.

Emanuele Panatta, Alessio Butera, Eleonora Mammarella, Consuelo Pitolli, Alessandro Mauriello, Marcel Leist, Richard A Knight, Gerry Melino, Ivano Amelio.

Gene-environment interactions can perturb the epigenome, triggering network alterations that participate in cancer pathogenesis. Integrating epigenomics, transcriptomics, and metabolic analyses with functional perturbation, we show that the tumor suppressor p53 preserves genomic integrity by empowering adequate levels of the universal methyl donor S-adenosylmethionine (SAM). In p53-deficient cells, perturbation of DNA methylation promotes derepression of heterochromatin, massive loss of histone H3-lysine 9 methylation, and consequent upregulation of satellite RNAs that triggers R-loop-associated replication stress and chromosomal aberrations. In p53-deficient cells, the inadequate SAM level underlies the inability to respond to perturbation because exogenous reintroduction of SAM represses satellite elements and restores the ability to cope with stress. Mechanistically, p53 transcriptionally controls genes involved in one-carbon metabolism, including Slc43a2, the methionine uptake transporter that is critical for SAM synthesis. Supported by clinical data, our findings shed light on the role of p53-mediated metabolism in preventing unscheduled R-loop-associated genomic instability.

Keywords: CP: Molecular biology; cancer; chromosome stability; epigenetic integrity; p53; tumor suppression

DOI: https://doi.org/10.1016/j.celrep.2022.111568