Inhibition of DNMT1 and ERRα crosstalk suppresses breast cancer via derepression ofIRF4

DNA methylation is implicated in the acquisition of malignant phenotypes, and the use of epigenetic modulating drugs is a promising anti-cancer therapeutic strategy. 5-aza-2'deoxycytidine (decitabine, 5-azadC) is an FDA-approved DNA methyltransferase (DNMT) inhibitor with proven effectiveness against hematological malignancies and more recently triple-negative breast cancer (BC). Herein, genetic or pharmacological studies uncovered a hitherto unknown feedforward molecular link between DNMT1 and the estrogen related receptor alpha (ERR alpha), a key transcriptional regulator of cellular metabolism. Mechanistically, DNMT1 promotes ERR alpha stability which in turn couples DNMT1 transcription with that of the methionine cycle and S-adenosylmethionine synthesis to drive DNA methylation. In vitro and in vivo investigation using a pre-clinical mouse model of BC demonstrated a clear therapeutic advantage for combined administration of the ERR alpha inhibitor C29 with 5-azadC. A large-scale bisulfite genomic sequencing analysis revealed specific methylation perturbations fostering the discovery that reversal of promoter hypermethylation and consequently derepression of the tumor suppressor gene,IRF4, is a factor underlying the observed BC suppressive effects. This work thus uncovers a critical role of ERR alpha in the crosstalk between transcriptional control of metabolism and epigenetics and illustrates the potential for targeting ERR alpha in combination with DNMT inhibitors for BC treatment and other epigenetics-driven malignancies.