Research Paper|Volume 12, Issue 10|pp 9745—9760

Loss of macroH2A1 decreases mitochondrial metabolism and reduces the aggressiveness of uveal melanoma cells

Sebastiano Giallongo^1,^2,³, Michelino Di Rosa¹, Rosario Caltabiano⁴, Lucia Longhitano¹, Michele Reibaldi⁵, Alfio Distefano¹, Oriana Lo Re^2,³, Angela Maria Amorini¹, Lidia Puzzo⁴, Lucia Salvatorelli⁴, Stefano Palmucci⁵, Daniele Tibullo¹, Andrea Russo⁵, Antonio Longo⁵, Giacomo Lazzarino⁶, Giovanni Li Volti^1,⁷, Manlio Vinciguerra²

¹Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
²Center for Translational Medicine (CTM), International Clinical Research Center (FNUSA-ICRC), St Anne's University Hospital, Brno, Czech Republic
³Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
⁴Department G.F. Ingrassia, Section of Anatomic Pathology, University of Catania, Catania, Italy
⁵Department of Ophthalmology, University of Catania, Catania, Italy
⁶UniCamillus-Saint Camillus International University of Health Sciences, Rome, Italy
⁷EuroMediterranean Institute of Science and Technology, Palermo, Italy

* Equal contribution

Received: January 29, 2020Accepted: March 31, 2020Published: May 12, 2020

https://doi.org/10.18632/aging.103241

Copyright © 2020 Giallongo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Uveal melanoma (UM) is the most common primary intraocular tumour in adults. The most accurate prognostic factor of UM is classification by gene expression profiling. Currently, the role of epigenetics is much less defined compared to genetic mechanisms. We recently showed a strong prognostic role of the expression levels of histone variant macroH2A1 in UM patients. Here, we assessed the mechanistic effects of macroH2A1 on UM progression.

UM cell lines were stably knocked down (KD) for macroH2A1, and proliferation and colony formation capacity were evaluated. Mitochondrial function was assayed through qPCR and HPLC analyses. Correlation between mitochondrial gene expression and cancer aggressiveness was studied using a bioinformatics approach.

MacroH2A1 loss significantly attenuated UM cells proliferation and aggressiveness. Furthermore, genes involved in oxidative phosphorylation displayed a decreased expression in KD cells. Consistently, macroH2A1 loss resulted also in a significant decrease of mitochondrial transcription factor A (TFAM) expression, suggesting impaired mitochondrial replication. Bioinformatics analyses uncovered that the expression of genes involved in mitochondrial metabolism correlates with macroH2A1 and with cancer aggressiveness in UM patients. Altogether, our results suggest that macroH2A1 controls UM cells progression and it may represent a molecular target to develop new pharmacological strategies for UM treatment.