Kam C. Yeung, Ph.D.
Kam C. Yeung, Ph.D.
The major focus of our research program is to understand the molecular basis of cell signaling on cellular as well as organismal levels. In metazoan each individual cell is related to others by the interplay of numerous signaling pathways. Dyregulation of signaling pathways often affects cellular homeostasis leading to different pathological conditions including cancers. Ongoing projects include:
1. Role of chemokines in RKIP mediated suppression of breast cancer metastasis
Raf kinase inhibitor protein (RKIP) is a novel metastasis suppressor gene in breast cancer and its expression is diminished in breast cancer metastases. Restoring RKIP expression is sufficient to inhibit cancer metastasis in experimental mouse models suggesting RKIP can function alone to regulate metastasis. However, the mechanisms through which loss of RKIP promotes metastasis are not well defined. RKIP expression negatively correlates with the expression of three chemokines. Because of the proven causal role of these chemokines in cancer metastasis it is possible that RKIP may inhibit metastasis by targeting multiple chemokines. In this project we propose to define the mechanisms through which loss of RKIP promotes metastasis and determine the clinical validity of findings using human breast cancer tissues. We will examine the possible roles of the three chemokines in RKIP-mediated suppression of breast cancer metastasis using both a cell-based invasion assay and an orthotopic implant mouse model. Chemokines play a pivotal role in shaping a tumor microenvironment that is conducive to tumor invasion and metastasis. We will examine effect of RKIP expression on tumor microenvironment and determine if the effect is chemokines dependent. We will also determine the mechanisms by which RKIP regulates expression of chemokines by a combination of loss-of-function and gain-of-function approaches as well as through epistatic analysis. Finally, we will use DNA and tissue microarray (TMA) to examine the expression of RKIP and chemokines in human breast cancer and correlating their expression with patient survival.
2. RKIP function in prostate cancer progression
Recent molecular and genetic profiling has identified oncogenic alterations in both PI3K and Ras/Raf signaling pathways as two of the critical events in prostate cancer progression. We observed that the expression of a cellular protein, RKIP, correlated with the oncogenic activation of the PI3K and Ras/Raf pathways. Importantly, germ-line deletion of RKIP increases incidence of prostate cancer and promotes metastasis in a transgenic mouse model driven by PI3K and Ras/Raf mutations. However it is not clear whether RKIP expression has an autonomous effect on prostate cells oncogenic transformation. It is also not clear whether RKIP inhibits prostate carcinogenesis by impinging on PI3K and Ras/Raf pathways. In this project we will define the facilitative role of RKIP in prostate cancer progression and metastasis driven by PI3K and Ras/Raf oncogenic mutations, elucidate the mechanism of RKIP function and examine the relationships between RKIP expression and PI3K/Ras/Raf activities in patient-derived samples. We will determine the add-in and knock-out effect of RKIP on prostate cancer in two well-established genetically engineered mouse (GEM) models (TRAMP and Pten-/-;K-rasG12V). We will identify the genes and molecular pathways that contribute to the enhanced PCa growth phenotype in RKIP-/-;TRAMP+ mice. We will also directly test if the activation of Ras/Raf pathway is the cause of the accelerated cancer phenotypes observed in RKIP knockout prostate oncogenic mice. Finally, we will use cancer gene microarray analysis and tissue microarray (TMA) study to examine the relationships of RKIP expression and PI3K/Ras/Raf pathways in clinical prostate samples.
3. Determine the causal role of miR-10b in BRafV600E-driven melanoma
This project focuses on elucidating the function of micro-non-coding RNAs (miRNAs) in the malignant transformation of melanocytes into melanoma. Recent high-throughput-sequencing of cancer genome has identified oncogenic mutations in BRaf genetic locus as one of the critical events in melanomagenesis. Although it is clear that the proliferation and survival of BRaf mutated melanoma cells are stringently dependent on BRaf-MEK-ERK activation, the downstream effector targets that are required for oncogenic BRaf-mediated melanomagenesis is not well defined. miRNAs have regulatory functions towards the expression of genes that are important in carcinogenesis. We observed that miR-10b expression correlates with the presence of oncogenic BRaf (BRafV600E) mutation in melanoma. Results of our in vitro cell-based experiments suggest that miR-10b is an important mediator of oncogenic BRafV600E activity in melanoma. To define the causal role of miR-10b, we will determine the add-in and knock-down effect of miR-10b on melanoma in genetically engineered mouse models. We will also examine the relationship between the expression of the miR-10b and BRafV600E mutation in clinical nevus and melanoma samples.
B.Sc. 1986 Basic Medical Sciences, University of South Alabama, Mobile, AL
Ph.D. 1990 Microbiology, University of South Alabama, Mobile, AL
1990 - 1992 Post-Doc, Molecular Virology, University of Iowa, Iowa City, IA
1992 - 1996 Post-Doc, Biochemistry, Howard Hughes Medical Institute/UMDNJ, Piscataway, NJ
2009-pre Associate Professor, Biochemistry & Cancer Biology, University of Toledo College of Medicine & Life Sciences, Toledo, OH
2001-2009 Assistant Professor, Biochemistry & Cancer Biology, University of Toledo Health Science Campus, Toledo, OH
1996-2001 Research Assistant Professor, Dept. of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, RI
Escara-Wilke, J., Keller, J.M., Woods Ignatoski, K.M., Dai, J., Shelley, G., Mizokami, A., Zhang, J., Yeung, M.L., Yeung, K.C. and Keller, E.T. (2015) Raf kinase inhibitor protein (RKIP) deficiency decreaes latency of tumorigenesis and increases metastasis in a murine genetic model of prostate cancer. Prostate 75:292-302.
Datar, I., Tegegne, H., Qin, K., Al-Mulla, F., Bitar, M.S., Trumbly, R.J., and Yeung, K.C. (2014) Gentic and epigenetic control of RKIP transcription. Crit. Rev. Oncogen. 19:417-430.
Lee, J., Yun, J., Yeung, K.C.,Bevilacqua, E., Balazsi, G., and Rosner, M.R. (2014) BACH1 and RKIP participate in a bistable network that affects progression to metastasis in breast cancer. Proc. Natl. Adac. Sci. USA 111:e364-373.
Yousuf, S., Duan, M.L., Moen, E.L., Cross-Knorr, S., Brilliant, K., Hixson, D.L., Bonavida, B., LaValle, T., Yeung, K.C., Chin, E., and Chatterjee, D. (2014) Raf kinase inhibitor protein (RKIP) prevents signal transducer and activtor of transcription 3 (STAT3) activationin breast and prostate cancer. PLoS One 9:e92478.
Marathe, H.G., Mehta, G., Zhang, X., Datar, I., Mehrotra, A., Yeung, K.C. and de la Serna, I.L. (2013) SWI/SNF enzymes promote SOX10-mediated activationof myelin gene expression. PLoS One 8:e69037.
Al-Mulla, F., Bitar, M.S., Al-Ali, Zainab, T., and Yeung, K.C. (2013) RKIP: Much more than Raf kinase inhibitory protein. J Cell Phys 228:1688-1702.
Ren, G., Feng, J., Datar, I., Yeung, A.H., Saladi, S.V., Feng, Y., de la Serna, I., and Yeung, K.C. (2012) A micro-RNA connection in BRaf(V600E)-mediated premature senescence of human melanocytes. Int. J. Cell Biol. 2012:913242.
Escara-Wilke, J., Yeung, K.C., and Keller, E.T. (2012) Raf kinase inhibitor protein (RKIP) in cancer. Cancer Metastasis Rev 31:615-620.
Zhang, H., Wu, J., Keller, J.M. Yeung, K.C., Keller, T.T., and Fu, Z. (2012) Transcriptional regulation of RKIP expression by androgen in prostate cells. Cell Physiol. Biochem. 30:134-1350.
Al-Mulla, F., Bitar, M.S., Feng, J., Park, S., and Yeung, K.C. (2012) A new model for raf kinase inhibitory protein induced chemotherapeutic resistance. PLoS 7:e29532
Ren, G., Feng, J., Datar, I., Yeung, A.H., Saladi, V., Feng, Y., de la Serna, I., and Yeung, K.C. (2011) A micro-RNA connection in BRafV600E-mediated premature senescence of human melantocytes. Int J Cell Biol 2012:913242
Park, S., Tang, H., and Yeung, K.C. (2011) A dual role of RKIP in NF-kB signaling pathways, Forum on Immunopathological Diseases and Therapeutics 2: 21-34.
Ren, G., Baritaki, S., Marathe, H., Feng, J., Park, S., Beach, S., Bazeley, P., Beshir, A.B., Fenteany, G., Mehra, R., Daignault, S., Al-Mulla, F., Keller, E., Bonavida, B., de la Serna I., and Yeung, K.C. (2011) Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer. Cancer Res 72:3091-3014.
Tang, H., Park, S., Sun, S.C. Trumbly, R., Ren, G., Tsung, E., and Yeung, K.C. (2010) RKIP inhibits NF-kB in cancer cells by regulating upstream signaling components of the IkappaB kinase complex. FEBS Lett 584:662-668.
Beshir, A.W., Ren, G., Magpusao, A.N., Barone, L.M., *Yeung, K.C., and *Fenteany, G. (2010) Raf kinase inhibitor protein suppresses nuclear factor-kB dependent cancer cell invasion at the level of matrix metalloproteinase expression but not cell migration. Cancer Lett 299:137-149. *co-corresponding authors.
Baritaki, S., Yeung, K.C., Palladino, M., Berenson, J.M., and Bonavida, B. (2009) Pivotal roles of snail inhibition and RKIP induction by the proteasome inhibitor NPI-0052 in tumor cell chemo- immuno-sensitization. Cancer Res 2009: 69:8376-8385.
Tang, H., Yeung, K.C. (2008) TAK1 (TGFß-Activating Kinase 1) Atlas Genet Cytogenet Oncol Haematol. URL: http://AtlasGeneticsOncology.org/Genes/MAP3K7ID44ch6q15.html
McHenry, K., Montesano, R., Zhu, S., Beshir, A.B., Tang, H., Yeung, K.C. and Fenteany, G. (2008) Raf kinase inhibitor protein positively regulates cell-substratum adhesion while negatively regulating cell-cell adhesion. J. Cell. Biochem. 103(3):972-985.
Rath, O., Park, S., Tang, H.H., Banfield, M.J., Brady, R.L., Lee, Y.C., Dignam, J.D., Sedivy, J.M., Kolch, W. and Yeung, K.C. (2008) The RKIP (Raf-1 Kinase Inhibitor Protein) conserved pocket binds to the phosphorylated N-region of Raf-1 and inhibits the Raf-1-mediated activated phosphorylation of MEK. Cell Signal, 20:935-941.
Bonavida, S., Baritaki, S., Huerta-Yepez, S., Vega, M.I., Chatterjee, D. and Yeung, K.C. (2008) Novel therapeutic applications of Nitric Oxide donors in cancer: roles in chemo- and immuno-sensitization to apoptosis and inhibition of metastases. Nitric Oxid: Biology and Chemistry, 19:152-157.
Theroux, S., Pereira, M., Casten, K.S., Burwell, R.D., Yeung, K.C., Sedivy, J.M. and
Klysik, J. (2007) Raf kinase inhibitory protein knockout mice: Expression in the brain and olfaction
deficit. Brain Res. Bull. 71(6):559-567.
Baritaki, S., Katsman, A., Chatterjee, D., Yeung, K.C, Spandidos, D.A. and Bonavida, B. (2007) Regulation of tumor cell sensitivity to TRAIL-induced apoptosis by the metastatic supppressor RKIP via YY1 inhibition and DR4 up-regulation. J. Immun., 179(8):5441-5453.
Park, S., Rath, O., Beach, S., Xiang, X., Kelly, S.M., Luo, Z., Kolch, W. and Yeung, K.C. (2006) Regulation of RKIP binding to the N-region of Raf-1 kinase. FEBS Lett. 580(27):6405-6412.
Hindley, A.D., Park, S., Wang, L., Shah, K., Wang, Y., Hu, X., Shokat, K.M., Kolch, W., Sedivy, J.M. and Yeung, K.C. (2004) Engineering the serine/threonine protein kinase Raf-1 to utilize an orthogonal analogue of ATP substituted at the N6 position. FEBS Lett. 556:26-34.
Chatterjee, D., Bai, Y., Wang, Z., Beach, S., Mott, S., Roy, R., Braastad, C., Sun,
Y., Mukhopadhyay, A., Aggarwal, B.B., Darnowski, J., Pantazis, P., Wyche, J., Fu,
Z., Kitagwa, Y., Keller, E.T., Sedivy, J.M. and Yeung, K.C. (2004) RKIP sensitizes cancer cells to apoptosis. J. Biol. Chem. 279:17515-17523.
Keller, E.T., Fu, Z., Yeung, K.C. and Brennan, M. (2004) Raf kinase inhibitor protein: A prostate cancer metastasis suppressor gene. Cancer Lett. 30:131-137.
Odabaei, G., Chatterjee, D., Jazirehi, A.L., Goodglick, L., Yeung, K.C. and Bonavida, B. (2004) Raf-1 kinase inhibitor protein (RKIP): Structure, function, regulation of cell signaling and pivotal role in apoptosis. Advances in Cancer Research 91:169-200.
Park, S., Yeung, M., Beach, S., Shield, J. and Yeung, K.C. (2004) RKIP down-regulates B-Raf kinase activity in melanoma cancer cells. Oncogene 24:3535-3540.
Chatterjee, D., Schmitz, I., Krueger, A., Yeung, K.C., Kirchoff, S., Krammer, P.H.,
Peter, M.E., Wyche, J.H. and Pantazis, P. (2001). Induction of apoptosis in 9-nitrocamptothecin-treated DU145 human prostate carcinoma
cells correlates with de novo synthesis of CD95 and CD95 ligand and down-regulation
of c-FLIPshort. Cancer Res. 61:7148-7154.
Yeung, K.C., Rose, D.W., Dhillon, A.S., Yaros, D., Gustafsson, M., Chatterjee, D., McFerran, B., Wyche, J., Kolch, W. and Sedivy, J.M. (2001). Raf kinase inhibitor protein interacts with NF-kB-inducing kinase and TAK1 and inhibits NF-kB activation. Mol. Cell. Biol. 21:7207-7217.
Yeung, K.C., Janosch, P., McFerran, B., Rose, D., Mischak, H., Sedivy, J.M. and Kolch, W. (2000). The mechanism of suppression of the Raf/MEK/ERK pathway by the RKIP inhibitor protein. Mol. Cell. Biol. 20:3079-3085.
Yeung, K.C., Seitz, T., Li, S., Janosch, P., McFerran, B., Kaiser, C., Fee, F., Katsanakis, K.D., Rose, D.W., Mischak, H., Sedivy, J.M. and Kolch, W. (1999). Suppression of Raf-1 kinase activity and MAP kinase signaling by RKIP. Nature 401:173-177.