Abstract
Alpha-ketoglutarate-dependent dioxygenase (ALKBH) is a DNA repair gene involved in the repair of alkylating DNA damage. There are nine types of ALKBH (ALKBH1-8 and FTO) identified in humans. In particular, certain types of ALKBH enzymes are dioxygenases that directly reverse DNA methylation damage via transfer of a methyl group from the DNA adduct onto α-ketoglutarate and release of metabolic products including succinate and formaldehyde. Here, we tested whether ALKBH6 plays a significant role in preventing alkylating DNA damage and decreasing genomic instability in pancreatic cancer cells. Using an E. coli strain deficient with ALKB, we found that ALKBH6 complements ALKB deficiency and increases resistance after alkylating agent treatment. In particular, the loss of ALKBH6 in human pancreatic cancer cells increases alkylating agent-induced DNA damage and significantly decreases cell survival. Furthermore, in silico analysis from The Cancer Genome Atlas (TCGA) database suggests that overexpression of ALKBH6 provides better survival outcomes in patients with pancreatic cancer. Overall, our data suggest that ALKBH6 is required to maintain the integrity of the genome and promote cell survival of pancreatic cancer cells.
Highlights
Pancreatic cancer is the seventh leading cause of cancer-related death in the world (Bray et al, 2020)
The type of substrates used for the transfer of alkyl groups determines which ALKBH protein is involved at the DNA base lesions (Li et al, 2013), indicating the importance of different types of oxidative demethylation for cell survival
We have demonstrated that ALKBH6 partially complements ALKBdeficient E. coli and restores survival and growth, following the SN2 type of alkylating DNA damage-induced cytotoxicity
Summary
Pancreatic cancer is the seventh leading cause of cancer-related death in the world (Bray et al, 2020). The 5-year overall survival of patients is less than 10% (Conroy et al, 2011; Von Hoff et al, 2013). The extremely low 5year overall survival of patients is, in part, due to pancreatic cancer cells having several mechanisms of resistance to different chemotherapeutic treatments, one of which is their capacity to efficiently repair alkylating agent-induced DNA damage. Alkylating agents induce DNA damage at different genomic sites, which subsequently leads to lethal and/or mutagenic DNA base lesions. The major repair mechanisms for alkylation damage are direct DNA repair, base excision repair (BER), and mismatch repair (MMR) (Kondo et al, 2010).
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