Depletion of Fumarate Hydratase, an Essential TCA Cycle Enzyme, Drives Proliferation in a Two-Step Model

Balakrishnan Solaimuthu, Michal Lichtenstein, Arata Hayashi, Anees Khatib, Inbar Plaschkes, Yuval Nevo, Mayur Tanna, Ophry Pines*, Yoav D. Shaul*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Fumarate hydratase (FH) is an evolutionary conserved TCA cycle enzyme that reversibly catalyzes the hydration of fumarate to L-malate and has a moonlight function in the DNA damage response (DDR). Interestingly, FH has a contradictory cellular function, as it is pro-survival through its role in the TCA cycle, yet its loss can drive tumorigenesis. Here, we found that in both non-cancerous (HEK-293T) and cancerous cell lines (HepG2), the cell response to FH loss is separated into two distinct time frames based on cell proliferation and DNA damage repair. During the early stages of FH loss, cell proliferation rate and DNA damage repair are inhibited. However, over time the cells overcome the FH loss and form knockout clones, indistinguishable from WT cells with respect to their proliferation rate. Due to the FH loss effect on DNA damage repair, we assumed that the recovered cells bear adaptive mutations. Therefore, we applied whole-exome sequencing to identify such mutated genes systematically. Indeed, we identified recurring mutations in genes belonging to central oncogenic signaling pathways, such as JAK/STAT3, which we validated in impaired FH-KO clones. Intriguingly, we demonstrate that these adaptive mutations are responsible for FH-KO cell proliferation under TCA cycle malfunction.

Original languageAmerican English
Article number5508
JournalCancers
Volume14
Issue number22
DOIs
StatePublished - 9 Nov 2022

Bibliographical note

Publisher Copyright:
© 2022 by the authors.

Keywords

  • DNA damage
  • TCA cycle
  • cancer metabolism
  • fumarate hydratase

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