| IDH1 and IDH2 are most frequently mutated metabolic genes in human tumors. IDH1 and IDH2 mutations reduce a-KG and accumulate 2-HG, an antagonist of a-KG, inhibiting the activity of multiple a-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases, leading to genome-wide histone and DNA methylation alterations. Besides IDH1 and IDH2, two other Krebs cycle genes FH and SDH are mutated in a subset of human cancers, leading to accumulation of their substrates, fumarate and succinate, respectively. Here, we demonstrate that fumarate and succinate are structurally similar to a-KG and act as competitive inhibitors of multiple a-KG-dependent dioxygenases, including histone demethylases, prolyl hydroxylases, collagen prolyl-4-hydroxylases, and TET hydroxylases. Knock-down of FH and SDH by siRNA results in elevated intracellular levels of fumarate and succinate, respectively, which act as competitors of a-KG to broadly inhibit the activity of a-KG-dependent dioxygenases, and consequent alterations of genome-wide histone and DNA methylations. These epigenetic alterations associated with mutations of FH and SDH would affect the proliferation and/or differentiation of progenitor cells, thereby contributing to tumorigenesis.The TET family of methylcytosine dioxygenases catalyze oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) and promote DNA demethylation. How TET enzymes are recruited to specific locus in the genome is largely unknown. Here, we show that WT1, a sequence-specific zinc finger transcription factor involved in development, interacts physically with TET2 and recruits TET2 to its target genes to activate their expression. The interaction between WT1 and TET2 is disrupted by multiple recurrent mutations in TET2 derived from acute myeloid leukemia (AML). These results provide fundamental evidence to support the mutually exclusive manner between WT1 and TET2 mutations in AML. |
PDF Full Text Request