Zhao Shengyuan, Devega Rodan, Francois Aaliyah, Kidane Dawit
Division of Pharmacology and Toxicology, College of Pharmacy, Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX, United States.
Front Genet. 2021 Apr 7;12:635808. doi: 10.3389/fgene.2021.635808. eCollection 2021.
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 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, 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.
α-酮戊二酸依赖性双加氧酶（ALKBH）是一种参与修复烷基化DNA损伤的DNA修复基因。在人类中已鉴定出九种类型的ALKBH（ALKBH1 - 8和FTO）。特别是，某些类型的ALKBH酶是双加氧酶，可通过将DNA加合物上的甲基转移到α-酮戊二酸上，并释放包括琥珀酸和甲醛在内的代谢产物，直接逆转DNA甲基化损伤。在此，我们测试了ALKBH6在预防胰腺癌细胞中烷基化DNA损伤和降低基因组不稳定性方面是否发挥重要作用。使用ALKB缺陷的菌株，我们发现ALKBH6可弥补ALKB缺陷并增加烷基化剂处理后的抗性。特别是，人类胰腺癌细胞中ALKBH6的缺失会增加烷基化剂诱导的DNA损伤，并显著降低细胞存活率。此外，来自癌症基因组图谱（TCGA）数据库的分析表明，ALKBH6的过表达为胰腺癌患者提供了更好的生存结果。总体而言，我们的数据表明，ALKBH6是维持基因组完整性和促进胰腺癌细胞存活所必需的。
