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. Author manuscript; available in PMC: 2020 Feb 1.
Published in final edited form as: Semin Cell Dev Biol. 2019 May 22;98:15–25. doi: 10.1016/j.semcdb.2019.05.002

Figure 6. Tumorigenesis in FH-deficient cancer.

Figure 6

We hypothesise that tumorigenesis in FH-deficient cells is a multi-step process. First, upon FH loss, cells undergo a series of biochemical adaptations in order to compensate for the loss of FH and for the truncation of the TCA cycle. These compensatory changes support the elevation of intracellular fumarate, which in turn can lead to senescence due, at least in part, to oxidative stress. In parallel, fumarate can induce epigenetic changes, such as hypermethylation of p16, that can enable the bypass of senescence. The activation of additional oncogenic cascades, including those orchestrated by NRF2, ABL1, and HIF contribute to cellular transformation.