**6. Conclusions**

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 effective, less toxic, and better tolerated therapies.
