PHF8 Demethylates YY1 to Regulate Electron Transfer Chain Gene Transcription and License Mitochondrial Reactive Oxygen Species Production to Promote Cancer Cell Growth

Emerging evidence suggest that mitochondrial reactive oxygen species (mROS) production is tightly controlled by electron transport chain (ETC), and increased levels of ROS production is linked to cancer development. The ETC therefore represents a promising way of cancer treatment. However, the epigenetic mechanisms governing the transcription of ETC genes to drive mROS production and cell proliferation remain to be fully characterized in cancer cells. Here, we reported that, while well-known to use histone substrates to activate transcription, PHF8, a PHD Finger and Jumonji C (JmjC) domain-containing histone demethylase, also functions as a transcriptional co-repressor for a large set of ETC genes, driving mROS production and promoting growth of cancer cells. PHF8 repression of ETC gene transcription is mediated through its demethylation of the transcription factor Yin and Yang 1 (YY1) at a highly conserved lysine (K) residue, K258. Using a structure-based virtual screening combined with demethylase activity assays, we identified a potent and specific small molecule inhibitor, iPHF8, which targets the catalytic core of PHF8 and is effective in regulating the transcription of ETC genes and mROS production in multiple types of cancer cells. Furthermore, iPHF8 is potent in suppressing cancer cell growth in vitro and tumor growth in cell line- and patient-derived xenografts in mice. Taken together, our data uncover a key epigenetic mechanism underlying transcriptional regulation of ETC genes and mROS production, which involves PHF8 demethylation of its non-histone substrate YY1, and demonstrated that targeting PHF8 has great potential to treat cancers.