Cancer biology and drug development
Name:
Dr. Daiqing Liao
Email
dliao@ufl.edu
Phone
(352) 273-8188
Faculty Department/Division
UF Health Cancer Center
This project is primarily:
Basic
Research Project Description:
The research in the laboratory of Dr. Daiqing Liao focuses on oncogenic signaling, metabolism, and cancer epigenetics, includingthe discovery and development of small molecule inhibitors and degraders of histone deacetylases (HDACs) andacetyltransferases as cancer therapeutics.
Intracellular lipid production in cancer cells supplies lipids to synthesize cell membranes and signaling molecules during rapid cellproliferation and tumor growth. Cancer cells also utilize fatty acid oxidation (FAO) to generate ATP to meet their energy demand.Notably, different lipid metabolites can inhibit or trigger ferroptosis due to iron-dependent oxidation of polyunsaturated fatty acids(PUFAs). Therefore, identifying regulators maintaining the intricate balance of lipid biosynthesis required for cell proliferation andsurvival is critical in cancer biology and therapy. Lipid metabolism is regulated by two oncogenic signaling pathways: the RAS-RAF-MEK-MAPK and the mammalian target of rapamycin (mTOR) pathways. About 30% of all cancers harbor constitutively activemutations in KRAS, HRAS, or NRAS, resulting in hyperactive RAS-RAF-MEK-MAPK signaling to drive tumorigenesis, metastaticprogression, immune evasion, and resistance to therapy. KRAS regulates lipid uptake, lipid synthesis, and FAO. mTOR is aserine/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 andnegative cross-regulation.
The coordinated activity of both pathways is critical to sustained tumor growth. Notably, mTORC1 signaling inhibition enhancesRAS-RAF-MEK-MAPK signaling to promote cancer cell survival and proliferation. Furthermore, constitutive mTORC1 signalinginduces cell death when the supply of unsaturated FAs is limited. However, the molecular link for coordinating the activity of theRAS and mTOR signaling pathways remains poorly defined. Our recent study suggests the RAS and mTOR signaling appear toconverge to regulate the epigenetic regulator DAXX, which, in turn, governs gene expression underlying lipid metabolism, cellsurvival, proliferation, and tumorigenesis. We use in vitro and in vivo breast cancer models to elucidate the molecular mechanismsof this pathway and discover potential therapeutics targeting it. Protein lysine acetyltransferases (KATs) catalyze the acetyl attachment to lysine side chains of protein substrates such as histonesand 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 therapeutictargets. We have been interested in understanding the cell-biological functions of these enzymes in epigenetics and cancerbiology, as well as in discovering, characterizing, and optimizing novel small-molecule inhibitors of these enzymes for cancertherapy. We have discovered novel KAT and HDAC inhibitors. In collaboration with medicinal chemists, we have developed potentdegraders targeting class I HDACs, including proteolysis-targeting chimeras (PROTACs) and molecular glue degraders. We use invitro biochemical and cell-based assays to validate the activities of our inhibitors and degraders. We use mouse tumor models todetermine the in vivo anticancer efficacy of these compounds. Our ultimate goal is to translate the inhibitors and degraders to theclinic to benefit cancer patients.
Does this project have an international component or travel?
No