BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity

• Published in: EMBO molecular medicine Vol. 9; no. 10; pp. 1398 - 1414
• Main Authors: Tacconi, Eliana MC, Lai, Xianning, Folio, Cecilia, Porru, Manuela, Zonderland, Gijs, Badie, Sophie, Michl, Johanna, Sechi, Irene, Rogier, Mélanie, Matía García, Verónica, Batra, Ankita Sati, Rueda, Oscar M, Bouwman, Peter, Jonkers, Jos, Ryan, Anderson, Reina‐San‐Martin, Bernardo, Hui, Joannie, Tang, Nelson, Bruna, Alejandra, Biroccio, Annamaria, Tarsounas, Madalena
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2017; John Wiley & Sons, Inc; John Wiley and Sons Inc; Springer Nature
• Subjects: Acetaldehyde; Acetaldehyde - metabolism; Aldehyde Dehydrogenase, Mitochondrial - genetics; Aldehyde Dehydrogenase, Mitochondrial - metabolism; Animals; Backup software; BRCA1; BRCA1 Protein - genetics; BRCA1 Protein - metabolism; BRCA2; BRCA2 Protein - genetics; BRCA2 Protein - metabolism; Cancer; Cell death; Cell Line, Tumor; Disulfiram; disulfiram, acetaldehyde dehydrogenase; DNA Damage; EMBO03; EMBO28; Fanconi Anemia - genetics; Fanconi Anemia Complementation Group D2 Protein - genetics; Fanconi Anemia Complementation Group D2 Protein - metabolism; Fanconi's anemia; Fibroblasts; Health aspects; Homologous Recombination; Humans; Life Sciences; Mice; Mice, Nude; Physiological aspects; Rad51 Recombinase - genetics; Rad51 Recombinase - metabolism; replication stress; Research Article; Tumors; Xenograft Model Antitumor Assays; disulfiram, acetaldehyde dehydrogenase; replication stress; BRCA1; BRCA2; DNA damage; disulfiram; Brca2; acetaldehyde dehydrogenase; Brca1
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.201607446

Maintenance of genome integrity requires the functional interplay between Fanconi anemia (FA) and homologous recombination (HR) repair pathways. Endogenous acetaldehyde, a product of cellular metabolism, is a potent source of DNA damage, particularly toxic to cells and mice lacking the FA protein FANCD2. Here, we investigate whether HR‐compromised cells are sensitive to acetaldehyde, similarly to FANCD2‐deficient cells. We demonstrate that inactivation of HR factors BRCA1, BRCA2, or RAD51 hypersensitizes cells to acetaldehyde treatment, in spite of the FA pathway being functional. Aldehyde dehydrogenases (ALDHs) play key roles in endogenous acetaldehyde detoxification, and their chemical inhibition leads to cellular acetaldehyde accumulation. We find that disulfiram (Antabuse), an ALDH2 inhibitor in widespread clinical use for the treatment of alcoholism, selectively eliminates BRCA1/2‐deficient cells. Consistently,
Aldh2
gene inactivation suppresses proliferation of HR‐deficient mouse embryonic fibroblasts (MEFs) and human fibroblasts. Hypersensitivity of cells lacking BRCA2 to acetaldehyde stems from accumulation of toxic replication‐associated DNA damage, leading to checkpoint activation, G2/M arrest, and cell death. Acetaldehyde‐arrested replication forks require BRCA2 and FANCD2 for protection against MRE11‐dependent degradation. Importantly, acetaldehyde specifically inhibits
in vivo
the growth of BRCA1/2‐deficient tumors and
ex vivo
in patient‐derived tumor xenograft cells (PDTCs), including those that are resistant to poly (ADP‐ribose) polymerase (PARP) inhibitors. The work presented here therefore identifies acetaldehyde metabolism as a potential therapeutic target for the selective elimination of BRCA1/2‐deficient cells and tumors.
Synopsis
Treatment with acetaldehyde or with the alcohol‐deterrent disulfiram, which enhances acetaldehyde levels, selectively eliminates BRCA1/2‐deficient cells and tumors. Increasing cellular acetaldehyde might thus benefit cancer patients with BRCA1/2 mutations.
Acetaldehyde and disulfiram increased the levels of RPA foci and decreased replication fork progression, leading to accumulation of replication‐associated DNA damage specifically in BRCA2‐deficient cells.
The
Aldh2
gene encodes an aldehyde dehydrogenase with key roles in endogenous acetaldehyde detoxification.
Aldh2
gene deletion or its point mutation E487K associated with the ethanol‐induced flushing syndrome in humans causes proliferation arrest in cells lacking BRCA1/2 expression.
Growth of BRCA1/2‐defective tumors, including those that have acquired resistance to PARP inhibitors, is suppressed by acetaldehyde treatment.
Graphical Abstract
Treatment with acetaldehyde or with the alcohol‐deterrent disulfiram, which enhances acetaldehyde levels, selectively eliminates BRCA1/2‐deficient cells and tumors. Increasing cellular acetaldehyde might thus benefit cancer patients with BRCA1/2 mutations.