Deng laboratory focuses on addressing two fundamental questions of cancer biology: how normal cells become cancer cells, and how to selectively kill cancer cells. The Deng lab has been developing four major areas to study prostate cancer by employing a combination of multiple approaches, including conditional gene knock-out/knock-in, genome editing (CRISPR-Cas9), X-ray crystallography/Cryo-EM, and structure-based virtual screening combined with drug design and chemical synthesis.(1) Discovery of metabolic targets for currently incurable castration-resistant prostate cancer (CRPC) Through genetic and pharmacological studies, Deng laboratory demonstrated for the first time that hexokinase 2 (HK2)-mediated Warburg effect plays an important role in tumor growth of CRPC in vivo. Dr. Deng has been building a strong cross-functional collaboration team comprising medicinal chemists, structural and computational biologists to dissect the function of HK2-translation axis in prostate tumorigenesis and discover HK2-selective inhibitors to block HK2-driven tumor growth. Utilizing genetic screening and cell metabolomics, they have identified a crucial molecular target that switches Warburg effect into the mitochondrial-dependent oxidative phosphorylation (OXPHOS) signaling, which in turn is essential for prostate cancer cell survival and tumor development under tumor microenvironment. Various types of experimental models are being used to determine the function of cancer metabolic networks in prostate tumor initiation, progression and metastasis. (2) Structural and functional understanding of oncogene mRNA translation in prostate tumorigenesisPhosphatase and tensin homolog (PTEN) is a tumor suppressor gene that plays a key role in controlling oncogene mRNA translation through the human translation initiation eIF4E/eIF4G/eIF4A(eIF4F) complex. The Deng lab is interested in deciphering how the eukaryotic eIF4F complex regulates oncogene mRNA translation in prostate tumorigenesis using structural biology methods (X-ray crystallography and Cryo-electron microscopy) coupled with biological studies. The results from these studies will facilitate a structure-based discovery of small-molecule compounds disrupting the assembly of a functional eIF4F complex in prostate cancer cells to selectively block the PTEN loss-driven oncogenic protein synthesis axis and thus inhibit prostate tumor development in vivo.(3) Dissect the role of dysfunctional telomere-initiated immune response in prostate tumorigenesisTelomeres are nucleoprotein complex structures that protect chromosomal ends from being recognized as aberrant damaged DNA. Dysfunctional telomeres could arise either from progressive telomere attrition (telomere shortening) or when components of the telomeric DNA-binding proteins ("shelterin complex") are perturbed (telomere uncapping). The Deng lab has generated a novel in vivo prostate cancer mouse model to study the role of uncapped telomeres in tumorigenesis. Utilizing the genetically engineered mouse models, they have revealed that a dysfunctional telomere-initiated DNA damage response induces an intrinsic cell death signaling in cancer cells with a concurrent activation of innate immune checkpoints extrinsically to remarkably diminish prostate cancer cells. These unexpected studies could provide an effective targeting therapeutic strategy through telomere uncapping-initiated immune response to selectively erase prostate cancer cells.(4) Gain-of-function of mutant p53 in PTEN loss-driven prostate tumorigenesisThe recent comprehensive sequencing studies revealed that the TP53 gene encoding a tumor suppressor protein is mutated in over 40% of metastatic human prostate cancer. Alterations of TP53 in cancer cells occur predominantly through missense mutations, including six "hotspot" mutations carrying most frequently substitutes, which ultimately result in accumulation of a full-length mutant p53 protein.These mutant p53 proteins not only lead to loss of tumor suppressive function of wild-type p53, but also confer "gain-of-function" (GOF) oncogenic activities that enhance tumor progression and metastasis. Interestingly, the TP53 mutation and loss of PTEN co-exist in metastatic prostate cancer. Owing to technical challenges, a mouse model harboring loss of Pten but expression of a mutant p53 does not exist. To circumvent these deficiencies, the Deng lab has been developing prostate cancer mouse models using a combination of a Pten conditional knockout mouse, p53 conditional knock out and a mutant p53 "hot spot" (identified in prostate cancer patients) knock-in mouse model, in which expression of mutant p53 could be conditionally induced while the expression of wild type p53 and/or Pten could be conditionally deleted in a prostate tissue-specific manner. These mouse models would provide a therapeutic model for drug discovery in vivo and faithfully recapitulate the crucial roles that PTEN loss and mutant p53 expression play during prostate tumor initiation, progression, and metastasis in situ.
