Department of Cancer Biology

Kam C. Yeung, Ph.D.

kcy

Kam C. Yeung, Ph.D.
Associate Professor of Cancer Biology
kam.yeung@utoledo.edu


RESEARCH INTERESTS: 

Cancer accounted for nearly 1 of 4 deaths in the US in 2014. Although gains have been made in treating localized cancer, once cancer progresses to a metastatic state, death typically ensues. Specific classes of genes that either enhance or suppress the metastatic process have been identified. Together with John Sedivy (Brown University) and Walter Kolch (Systems Biology Ireland & Conway Institute University College Dublin), we identified and named Raf kinase inhibitor protein (RKIP) as one of the metastasis suppressor genes of breast and prostate cancer.  Our recent studies with transplantation mouse models demonstrated that RKIP inhibits cancer metastasis by modulating the expression of multiple metastasis genes. Unlike other classical tumor suppressor genes, which usually have complete loss-of-function mutations in tumor cells, RKIP is not mutated but merely silenced in cancer. Importantly, we demonstrated that the low expression levels of RKIP could be re-activated. In view of its role as a master modulator of expression of multiple metastasis genes and its expression being able to be re-activated, RKIP represents a novel therapeutic target for patients afflicted with metastatic cancer. To utilize this potential, the major focus of the lab is to understand the molecular mechanism through which RKIP exerts its control over multiple metastasis genes. To have immediate therapeutic gains in treatment of cancer metastasis, we are also interested in developing methods to restore expression of RKIP in cancers. Ongoing projects include:

Identifying mechanisms underlying the regulation of multiple metastasis genes by RKIP

Using both a cell-based invasion assay and cancer mouse models, we demonstrated that RKIP suppresses breast cancer metastasis by regulating multiple metastasis genes. We will determine the mechanisms by which RKIP regulates expression of metastasis genes by a combination of loss-of-function and gain-of-function approaches as well as through epistatic analysis. We will use patient derived tissue microarray (TMA) to examine the expression of RKIP and metastasis genes in human breast cancer, correlating their expression with patient survival. Breast cancer is the most common malignancy among females in the U.S.  Results should provide new understanding of its etiology in molecular detail and initiate studies aimed at dissecting the complex signaling network that is regulated by RKIP to suppress metastasis. The information gained from this research will offer a promising potential for identification of new cancer biomarkers and advancement in breast cancer therapy.

Characterization of miRNAs as negative regulator of the metastasis suppressor gene RKIP and target for anti-metastasis therapies in RKIP-deficient breast cancers

We identified three miRNAs as promising candidate regulators of RKIP expression in breast cancer. We will examine the possible roles of the identified miRNAs in regulating RKIP expression in breast cancer. This will be done by both loss-of-function and gain-of-function approaches, as well as through a combination of genetic and biochemical methods. We will also determine their in vivo role by exploring whether their deficiency have a facilitative role in RKIP-mediated suppression of breast cancer metastasis in cancer mouse models. This will be done by a loss-of-function approach as well as through epistatic analysis. Our results should provide new understanding of the complex regulatory post-transcriptional network that is responsible for down regulation of RKIP in breast cancer. The information gained from this research will offer a promising potential for identifying new molecular targets for therapy intervention to restore RKIP expression in breast cancer to inhibit metastasis.

EDUCATION:

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

ACADEMIC APPOINTMENTS:

2017-pres.  Assoc Professor, Dept. of Cancer Biology, Univ of Toledo College of Medicine & Life Sciences, Toledo, OH
2009-2017 Assoc Professor, Dept. of Biochemistry & Cancer Biology, Univ of Toledo College of Medicine & Life Sciences, Toledo, OH
2001-2009 Assistant Professor, Dept. of Biochemistry & Cancer Biology, Univ of Toledo Health Science Campus, Toledo, OH
1996-2001 Research Assistant Professor, Dept. of Molecular Biology, Cell Biology & Biochemistry, Brown Univ, Providence, RI

REPRESENTATIVE PUBLICATIONS:

Datar, I., Feng, J.W., Qiu, X., Lewandowski, J., Yeung., M.L., Ren, G., Aras, S., Al-Mulla, F., Cui, H., Trumbly, R.J., Arudra, S.K.C., de la Casas, L., de la Serna, I.L., Bitar, M.D., and Yeung, K.C. (2015) RKIP inhibits local breast cancer invasion by antagonizing the transcriptional activation of MMP13.PLoS One 10:e0134494.

Datar, I., Qiu, X., Ma, H.Z., Yeung, M.L., Aras, S., de la Serna, I., Al-Mulla, F., Tan, T.Z., Theiery, J.P., Bitar, M.S., Trumbly, R.J., Fan, X., Cui, H., and Yeung, K.C. (2015) RKIP regulates CCL5 expression to inhibit breast cancer invasion and metastasis by controlling macrophage infiltration. Oncotarget 6:39050-39061.

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 decreases 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 activator of transcription 3 (STAT3) activation in 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 expressionPLoS 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 proteinJ 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 proteosome 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

Beach, S., Tang, H., Park, S., Dhillon, A.S., Keller, E.T., Kolch, W. and Yeung, K.C. (2008) Snail is a repressor of RKIP transcription in metastatic prostate cancer cells.  Oncogene, 27:2343-2348.


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 suppressor 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.

 

Last Updated: 11/3/17