The lab is using molecular, cellular, biochemical, genetic, structural, 'omics', bioinformatics and imaging approaches to studying how cancer cell behaviors are regulated at the transcription and epigenetic levels. The ultimate goal is to develop novel anti-cancer agents for cancer treatment. We have developed several research programs that are integrated with technology development, basic biological research, and clinical translation.
The current technology developments involve bimolecular fluorescence complementation (BiFC) and BiFC-derived technologies. The biological research is centered on the transcriptional and epigenetic regulation of cancer cell growth and therapeutic response. The clinical translational research is aimed at understanding the molecular mechanisms of therapy-resistant prostate cancer and development of novel therapeutics. In addition, we are developing novel treatment approaches for lung cancer and pancreatic cancer.
Regulation of gene expression at the transcriptional and epigenetic level is a key process to determine how cells respond to intracellular and extracellular signals. Because of this, deregulation of transcription factors and epigenetic regulators is often implicated in many human diseases such as cancer. We use molecular, cellular, biochemical, genetic, "Omics", structural, bioinformatics and imaging approaches to identifying novel and unique molecular interactions at the transcriptional and epigenetic level that regulate the growth of cancer cells, determine the response of cancer cells to therapy, and confer the resistance to treatment. The ultimate goal is to develop novel therapeutics to treat cancer.
(1) Development of novel technologies to image and target transcriptional and epigenetic regulation.
Many transcription factors form dimers among the family members to bind DNA and regulate gene expression. Although genetic approach has been used as a gold standard to analyze the role of genes in vivo, it suffers from several drawbacks when transcription factor-encoding genes are knocked out or knocked down. We have been developing a series of bimolecular fluorescence complementation (BiFC)-based technologies to visualize and target transcription factor dimers, rather than individual proteins or genes. We will continue to explore novel BiFC applications in the context of cancer. These applications include, but not limited to, BiFC-based biosensors, high throughput screening for protein-protein interaction disruptors and BiFC-based interactomes. We believe the development and application of novel technologies will allow us to identify molecular targets and pathways for the development of novel cancer therapeutics.
(2) Regulation and function of AP-1 in prostate cancer cells.
We have been applying our novel technologies to investigate how activator protein 1 (AP-1) dimers function in mammalian cells. We are also using C. elegans as a genetic model to assess the roel of AP-1 dimers in vivo. The use of novel technologies has allowed us to make several novel discoveries regarding the role of AP-1 dimers and their target genes in cells. We are currently investigating the regulation and functional consequences of altered expression and subcellular localization of AP-1 proteins (c-Jun, c-Fos and ATF2) in prostate cancer cells.
(3) Mechanisms and targeting of radiotherapy-induced neuroendocrine differentiation (NED) in prostate cancer.
By mimicking a clinical radiotherapy protocol (2 Gy/day, 5 days/week for 7 weeks), we subjected prostate cancer cells to fractionated ionizing radiation (FIR). Surprisingly, we found that upon 4-week irradiation, almost all survived cells differentiated into neuroendocrine-like (NE-like) cells, a process also known as neuroendocrine differentiation (NED). Because NED is associated with disease progression and therapy resistance and because NED is reversible, our finding provides evidence to suggest that radiotherapy-induced NED may represent a novel mechanism by which prostate cancer cells survive treatment and contribute to recurrence. We have identified several critical transcriptional and epigenetic regulators of radiation-induced NED (Cancer Res, 2008, Am J Cancer Res, 2011 and 2014). Our current effort is to further validate these critical regulators as therapeutic targets for development of novel radiosensitizers.
(4) Role of PRMT5 in prostate cancer development, progression and therapeutic response.
Using a proteomic approach, we have identified protein arginine methyltransferase 5 (PRMT5) as a critical regulator of radiation-induced NED. We have also discovered that PRMT is an important epigenetic regulator of prostate cancer cell growth. We are using multidisciplinary approaches to elucidating the role of PRMT5 in prostate cancer development, progression and therapeutic response.
(5) Development of protein-protein interaction disruptors as novel cancer therapeutics.
Protein-protein interactions are essential elements of signal transduction. Identification of unique protein-protein interactions in cancer cells represents an attractive, though challenging, approach to developing novel anti-cancer agents. We have been employing BiFC-based approaches to identifying novel and unique protein-protein interactions in cancer cells. In collaboration with computational biologists and medicinal chemists, we are currently developing BiFC-based high throughput screening approach to screening for inhibitors of several unique protein-protein interactions that regulate prostate cancer growth and radiation response.