**Author details**

*Pheochromocytoma, Paraganglioma and Neuroblastoma*

effective, less toxic, and better tolerated therapies.

Cáncer, CIBERONC, Instituto de Salud Carlos III (ISCIII).

**6. Conclusions**

**Acknowledgements**

**Conflict of interest**

There are not conflict of interest.

**Notes/thanks/other declarations**

**Acronyms and abbreviations**

DNMT DNA methyltransferase

HDR homology-dependent DNA repair LRES Long-range epigenetic silencing PARP poly [ADP-ribose] polymerase

PRC2 polycomb repressive complex 2 SDH succinate dehydrogenase TCA tricarboxylic acid cycle TCGA The cancer genome atlas

PPGL paraganglioma and pheochromocytoma

supplementation, has been shown to result in inhibited growth of hypersuccinylated tumors [59], thus shedding lights on alternative approaches for *SDHx*-mutated-PPGLs.

Metastasis is the most letal attribute of PPGLs, especially in patients with compromised SDH activity. Since the initial discovery of succinate as an oncometabolite that induces DNA hypermethylation, the knowledges that illustrate its role on epigenetic reprogramming and metastasis development continues to expand. The best characterized changes, DNA and histone methylation, could be efficiently and globally neutralized by DNA or histone hypomethylating agents, well-known epi-drugs that could be tested as single- or multi-drug therapy in metastatic SDHdeficient PPGLs. The activity of these epigenetic therapies, however, is not limited to cancer cells but have broad cellular effects leading to global loss of DNA methylation and off-target effects. Emerging scientific knowledges on the impacts that succinate-induced modification of the epigenetic code has on cancer development and progression is certainly empowering the research community to develop more

MDC is funded by Fondo de Investigación Sanitaria (grant numbers FIS PI17/01901 and PI20/01754) and the Red Temática de Investigación Cooperativa en

L.C. thanks the Spanish Ministerio de Ciencia, Innovación y Universidades for the FPU predoctoral contract. T.C. thanks to the Red Temática de Investigación Cooperativa en Cáncer, CIBERONC, Instituto de Salud Carlos III (ISCIII) for her contract. A.S.J.M. thanks to Principado de Asturias and Fondo Europeo de Desarrollo Regional (GRUPIN) for his contract. **Figures 1**–**3** were created with BioRender.com.

**38**

María-Dolores Chiara1,2,3\*, Lucía Celada1,3, Andrés San José Martinez1 , Tamara Cubiella1,3, Enol Álvarez-González1,2,4 and Nuria Valdés1,5

1 Institute of Sanitary Research of Principality of Asturias, Oviedo, Spain

2 Institute of Oncology of the Principality of Asturias, University of Oviedo, Oviedo, Spain

3 CIBERONC, Madrid, Spain

4 Department of Functional Biology, University of Oviedo, Oviedo, Spain

5 Section of Endocrinology and Nutrition, Hospital Universitario de Cabueñes, Gijón, Spain

\*Address all correspondence to: mdchiara.uo@uniovi.es

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
