M.S. (1987) -Tongji Medical University, China (Cancer Immunology)
Ph.D. (1997) - Kobe University, Japan (Molecular Biology)
Postdoc (2000-2002) - University of Michigan
Research Investigator (2002-2003) - University of Michigan
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" 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 suggests 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 radiosensizers.
(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.
To learn more about our research, please visit our lab homepage at https://www.changdenghulab.com
Xuehong Deng (Lab Technician VII)
Jun Hao (Graduate Student)
Yi Liu (Visiting Scholar)
Jacob Louis Owens (Graduate Student)
Qi Shen (Visiting Scholar)
Samantha Lauren (Sam) Tinsley (PULSe Graduate Student)
Elena Beketova Wild (PULSe Graduate Student)
Jie Yang (Visiting Scholar)
Vickman, R.E., Yang, J., Lanman, N.A., Cresswell, G.M., Zheng, F., Zhang, C., Doerge, R.W., Crist, S.A., Mesecar, A.D., Hu, C.D., and Ratliff, T.L. Mol Cancer Res, 17:1253-1263 (2019)
Zeng, L., Wang, W.H., Arrington, J., Shao, G., Geahlen, R.L., Hu, C.D. and Tao, W.A. Identification of upstream kinases by fluorescence complementation mass spectrometry. ACS Central Sci, http://pubs.acs.org/doi/pdf/10.1021/acscentsci.7b00261 (2017)
Deng, X., Shao, G., Zhang, H.T., Li, C., Zhang, D., Cheng, L., Elzey, B.D., Pili, R., Ratliff, T.L., Huang, J. and Hu, C.D. Protein arginin methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growth. Oncogene, 36:1223-1231 (2017).
Vickman, R.E., Christ, S.A., Kerian, K., Eberlin, L., Coos, R.G., Burcham, G.N., Buhman, K.K., Hu, C.D., Mesecar, A.D., Cheng, L., Ratliff, T.L. Cholesterol sulfonation enzyme, SULT2B1b, modulates AR and cell growth proerties in prostate cancer. Mol Cancer Res, 14:776-789 (2016).
Zhang, H.T., Zheng, L.F., He, Q.Y., Tao, W.A., Zha, Z.G., and Hu, C.D. The E3 ubiquitin ligase CHIP mediates ubiquitination and proteasomal degradation of PRMT5. Biochim Biophys Acta 1863:335-346 (2016)
Pratt, E.P., Owens, J.L., Hockerman, G.H., and Hu, C.D. Bimolecular fluorescence complementation (BiFC) analysis of protein-protein interactions and assessment of subcellular localization in live cells. Methods Mol Biol, 1474:153-170 (2016)
Xu, D., Zhan, Y., Qi, Y., Cao, B., Bai, S., Xu, W., Gambhir, S.S., Lee, P., Sartor, O., Flemington, E.K., Zhang, H., Hu, C.D., and Dong, Y. Androgen receptor splice variants dimerize to transactivate target genes. Cancer Res 75:3663-3671 (2015).
Hu, C.D., Choo, R., and Huang, J. Neuroendocrine differentiation in prostate cancer: a mechanism of radioresistance and treatment failure. Front Oncol 5:90. doi: 10.3389/fonc.2015.00090
Suarez, C., Deng, X., and Hu, C.D. Targeting CREB inhibits radiation-induced neuroendocrine differentiation and increases radiation-induced cell death in prostate cancer cells. Am J Cancer Res 4:850-861 (2014)
Zhang, H.T., Zhang, D., Zha, Z.G., and Hu, C.D. Transcriptional regulation of PRMT5 by NF-Y is required for cell growth and negatively regulated by the PKC/c-Fos signaling in prostate cancer. Biochim Biophys Acta 1839:1330-1340 (2014)
Hsu, C., and Hu, C.D. Transcriptional activity of c-Jun is critical for the suppresson of AR function. Mol Cell Endocrinol 372:12-22(2013)
Ejendal, K.F.K., Conley, J.M., Hu, C.D. and Watts, V.J. Bimolecular fluorescence complementation analysis of G protein-coupled receptor dimerization in living cells. Methods Enzymol 521:259-270 (2013)
Kodama, Y. and Hu, C.D. Bimolecular fluorescence complementation (BiFC): How to calculate signal-to-noise ratio. Methods Cell Biol 113:107-121 (2013)
Kodama, Y. and Hu, C.D. Bimolecular fluorescence complementation (BiFC): A 5-year update and future perspectives. Biotechniques, 53:285-298 (2012)
Young MM, Takahashi Y, Khan O, Park S, Hori T, Yun J, Sharma AK, Amin S, Hu CD, Zhang J, Kester M, Wang HG. Autophagosomal membrane serves as platform for intracellular death-inducing signaling complex (iDISC)-mediated caspase-8 activation and apoptosis. J. Biol. Chem. 287:12455-12688 (2012)
Hsu, C. and Hu, C.D. Critical role of an N-terminal end nuclear export signal in regulation of ATF2 subcellular localization and transcriptional activity. J. Biol. Chem. 287:8621-8632 (2012)
Deng, X., Elzey, B.D., Poulson, J.M., Morrison, W.B., Ko, S.C., Hahn, N.M., Ratliff, T.L., and Hu, C.D. Ionizing radiation induces neuroendocrine differentiation in vitro, in vivo and in human prostate cancer patients. Am. J. Cancer Res. 1:834-844 (2011)
Xing, J., Wang, S., Lin, F., Pan, W., Hu, C.D., and Zheng, C. A comprehensive characterization of interaction complexes of Herpes Simplex Virus type I ICP22, UL3, UL4 and UL20.5. J. Virol. 85:1881-1886 (2011)
Kodama, Y. and Hu, C.D.. An improved bimolecular fluorescence complementation assay with a high signal-to-noise ratio. Biotechniques, 49:793-805 (2010)
Le, T.T, Duren, H.M., Slipchenko, M.N., Hu, C.D.*, and Cheng, J.X. Label-free quantitative analysis of lipid metabolism in living Caenorhabditis elegans. J. Lipid Res. 51:672-677 (2010) *Co-Corresponding Author
Hiatt, S.M., Duren, H.M. Shyu, Y., Ellis, R.E., Hisamoto, N., Matsumoto, K., Kariya, K., Kerppola, T.K., and Hu, C.D.. C. elegans FOS-1 and JUN-1 regulate plc-1 expression to control ovulation. Mol. Biol. Cell 20:3888-3895 (2009)
Yuan, Z., Gong, S., Song, B., Mei, Y., Hu, C., Li, D., Thiel, G., Hu, C.D., and Li, M. Opposing role for ATF2 and c-Fos in c-Jun-mediated apoptosis induced by potassium deprivation in cerebellar granule neurons. Mol. Cell. Biol. 29:2431-2442 (2009)
Deng, X., Liu, H., Huang, J., Cheng, L., Keller, E.T., Parsons, S.J., and Hu, C.D. Ionizing radiation induces prostate cancer neuroendocrine differentiation through interplay of CREB and ATF2: Implications for disease progression. Cancer Res. 68:9663-9670 (2008)
Shyu, Y. and Hu, C.D. Fluorescence complementation: an emerging tool for biological research. Trends Biotechnol. 26:622-630 (2008)
Shyu, Y., Suarez, C., and Hu, C.D. Visualization of ternary complexes in living cells by using a BiFC-based FRET analysis. Nat. Protoc. 3:1693-1702 (2008)
Shyu, Y., Fox, SM., Duren, HM., Ellis, R.E., Kerppola, T.K. and Hu, C.D. Visualization of protein interaction in living Caenorhabditis elegans using bimolecular fluorescence complementation (BiFC) analysis. Nat. Protoc., 4:588-596 (2008)
Shyu, Y., Suarez, C., and Hu, C.D. Visualization of AP-1-NF-κB ternary complexes in living cells by using a BiFC-based FRET. Proc. Natl. Acad. Sci. U.S.A., 105:151-156 (2008)
Liu, H., Deng, X., Shyu, Y., Li, J.J., Taparowsky, EJ., and Hu, C.D. Mutual regulation of c-Jun and ATF2 by transcriptional activation and subcellular localization. The EMBO J., 25:1058-1069 (2006).
Hu, C.-D. and Kerppola, T. Simultaneous visualization of interactions between multiple proteins in living cells using multicolor bimolecular fluorescence complementation analysis. Nat. Biotechnol. 21, 539-545 (2003).
Hu, C.-D. Chinenov, Y., and Kerppola, T Visualization of interactions among bZIP and Rel family proteins in living cells using bimolecular fluorescence complementation. Mol. Cell. 9, 789-798 (2002).