Daiqing Liao, PhD

The research in the laboratory of Dr. Daiqing Liao focuses on oncogenic signaling, metabolism, and cancer epigenetics, including the discovery and development of small molecule inhibitors and degraders of histone deacetylases (HDACs) and acetyltransferases as cancer therapeutics.

The RAS-RAF-MEK-MAPK and the mammalian target of rapamycin (mTOR) oncogenic signaling pathways drive tumorigenesis, metastatic progression, immune evasion, and resistance to therapy. RAS signaling regulates crucial pathways required for cancer cell proliferation, including metabolic pathways such as lipid uptake, lipid synthesis, and fatty acid oxidation (FAO). mTOR is a serine/threonine kinase acting as a key intracellular signaling hub to regulate nutrient homeostasis, metabolism, protein synthesis, and autophagy. The mTORC1 complex promotes lipogenesis. The RAS and mTOR signaling pathways exhibit both positive and negative cross-regulation. Our goal in this project is to understand how the epigenetic regulator and histone chaperone DAXX coordinates the RAS and mTOR signaling outputs, such as in lipid metabolism, for cancer cell survival, proliferation, and tumorigenesis. We use in vitro and in vivo breast cancer models to elucidate the underlying molecular mechanisms and discover potential therapeutics targeting the DAXX epigenetic pathway.

Protein lysine acetyltransferases (KATs) catalyze the acetyl attachment to lysine side chains of protein substrates such as histones and many other cellular proteins. Deacetylases (HDACs) catalyze the reverse reaction to remove the attached acetyl group. Acetylation of protein substrates impacts their stability and functions in various cellular pathways, such as gene transcription, intracellular trafficking, and metabolisms. KATs and HDACs are implicated in human diseases and represent rational therapeutic targets. We have been interested in understanding the cell-biological functions of these enzymes in epigenetics and cancer biology, as well as in discovering, characterizing, and optimizing novel small-molecule inhibitors of these enzymes for cancer therapy. We have discovered novel KAT and HDAC inhibitors. In collaboration with medicinal chemists, we have developed potent degraders targeting class I HDACs, including proteolysis-targeting chimeras (PROTACs) and molecular glue degraders. We use in vitro biochemical and cell-based assays to validate the activities of our inhibitors and degraders. We use mouse tumor models to determine the in vivo anticancer efficacy of these compounds. Our ultimate goal is to translate the inhibitors and degraders to the clinic to benefit cancer patients.