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Fumarate hydratase in cancer: A multifaceted tumour suppressor
Christina Schmidt1, Marco Sciacovelli1, Christian Frezza1
1Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, United Kingdom.
Abstract:
Cancer is now considered a multifactorial disorder with different aetiologies and outcomes. Yet, all cancers share some common molecular features. Among these, the reprogramming of cellular metabolism has emerged as a key player in tumour initiation and progression. The finding that metabolic enzymes such as fumarate hydratase (FH), succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH), when mutated, cause cancer suggested that metabolic dysregulation is not only a consequence of oncogenic transformation but that it can act as cancer driver. However, the mechanisms underpinning the link between metabolic dysregulation and cancer remain only partially understood. In this review we discuss the role of FH loss in tumorigenesis, focusing on the role of fumarate as a key activator of a variety of oncogenic cascades. We also discuss how these alterations are integrated and converge towards common biological processes. This review highlights the complexity of the signals elicited by FH loss, describes that fumarate can act as a bona fide oncogenic event, and provides a compelling hypothesis of the stepwise neoplastic progression after FH loss.
Insights
Loss of fumarate hydratase (FH) in cancer drives tumor growth by activating oncogenic pathways. Fumarate, a metabolite, acts as a key driver in tumorigenesis, explaining stepwise cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Pathways
Background:
- Cancer is a multifactorial disease with common molecular features, including metabolic reprogramming.
- Metabolic enzyme mutations (e.g., FH, SDH, IDH) suggest metabolic dysregulation can drive cancer.
- The precise mechanisms linking metabolic alterations to cancer initiation and progression are not fully understood.
Purpose of the Study:
- To review the role of fumarate hydratase (FH) loss in tumorigenesis.
- To elucidate the function of fumarate as an oncogenic activator.
- To explore how FH loss-induced alterations converge towards common biological processes.
Main Methods:
- Literature review of studies on fumarate hydratase (FH) and cancer.
- Analysis of molecular mechanisms linking fumarate accumulation to oncogenic signaling.
- Integration of data on metabolic dysregulation and tumorigenesis.
Main Results:
- Fumarate hydratase (FH) loss is a significant factor in tumor initiation and progression.
- Fumarate acts as a key activator of multiple oncogenic cascades.
- FH loss triggers a cascade of events leading to stepwise neoplastic progression.
Conclusions:
- Fumarate accumulation due to FH loss is a bona fide oncogenic event.
- Understanding FH loss provides insights into cancer's metabolic drivers.
- This review offers a hypothesis for neoplastic progression following FH loss.
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