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Hui-Kuan Lin Laboratory

Hui-Kuan Lin Small Photo


  • B.S. Pharmacy, National Taiwan University, Taipei, Taiwan, 1993
  • M.S. Pharmacology, National Taiwan University, Taipei, Taiwan, 1995
  • Ph.D. Pathology (Cancer Biology), University of Rochester, Rochester, New York, 2002
  • Postdoctoral training, Memorial Sloan-Kettering Cancer Center, New York, NY, 2002-2007


Research Interest

  • Crosstalk between oncogenic and tumor supressor networks
  • Posttranslational modifications
  • Cancer progression and metastasis
  • Biology of normal and cancer stem cells
  • Metabolism and cancer
  • Drug discovery for cancer

This laboratory would provide experience with the mouse genetics in cancer development, molecular biology and cell biology techniques, and transgenic mice techniques and drug development.

A. Ubiquitination in diverse signaling and cancers. Ubiquitination pathways are important posttranslational modifications invovled in diverse biological processes. It has been well established that ubiquitination serves as a key mode for orchestrating protein stability and degradation. However, recent studies from my group and others have revealed novel roles of ubiquitination in non-proteolytic functions. We have shown that K63-linked ubiquitination of Akt facilitates Akt membrane localization and subsequent activation in response to diverse growth factors (Science, 2009). Interestingly, we found distinct growth factors utilize diverse E3 ligases to elicit Akt ubiquitnation for Akt activation (Cell, 2012). Importantly, the cancer-associated Akt mutant-Akt E17K, recently identified in a subset of human cancers, displays enhanced K63-linked ubiquitination of Akt, in turn contributing to Akt hyperactivation, suggesting a role for Akt ubiquitination in aberrant Akt activation and cancer development (Science, 2009; Cell, 2012). Thus, this novel posttranslational modification of Akt represents an exciting and novel avenue for cancer research that has advanced our current understanding of how Akt signaling activation is regulated. In addtion to study how ubiquitination regulate growth factor receptors/kinase singaling, we are also exploring the role of non-proteolytic ubiquitination in devierse molecular and biological processes including DNA damage signaling and repair, protein trafficking, and epigenetic and trancriptional regulaiton. We believe such study will not only offer new insights for signaling control, but also lead to novel therapeutic targets for cancer.

B. Cancer progression and metastasis. We are particularly interested in dissecting the genetic networks between oncogenes and tumor suppressor in cancrer progression and aim to identify the key upstream regulators and downstream effector involved in this process. In particular, we have recently identified Skp2 E3 ligase serves as a critical player for cancer development upon conditional Pten loss and/or Neu overexpression using genetic mouse models (Nature, 2010; Cell, 2012). Cancer metastasis is a complex process involving several key steps that enable disseminating primary cancer cells to colonize at distant sites. Metastasis causes the majority of deaths in patients with cancer, and treatment of this devastating form of the disease remains a major challenge. Although cancer metastasis has been under intensive focus recently, how this event occurs and the genetic programs responsible for it remain elusive. The research interest in my lab is to define genetic programs that dictate cancer metastasis using biochemical and molecular biology approaches along with genetic mouse modeling. We have recently identified a transcrptional complex network critical for breast cancer metastasis (Nat. Cell Biol, 2010). Our studies not only provided novel molecular insight into how cancer metastasis is regulated but also offered new paradigms and therapeutic targets for cancer metastasis.

C. Metabolism in Cancer progression and Cancer Stem Cell. Recently studies suggest that cancer cells and normal cells display distinct metabolic states. The outstanding question remains to be addressed is whether such disitcnt metabolic may dictate cancer progression and cancer stem cell maintenance. Our lab is now atively pursuing this line of the research by using systematic approaches including proteomics and metablomics, molecular and biochemical approaches, along with genetic mouse models and human cancer samples.

D. Develop small molecules targeting ubiquitination pathways. Our laboratory has identified several E3 ligases as key players in oncogenic signaling and cancer regulation (Science, 2009; Cell, 2012). The next goal is to develop small molecule inhibitors to target those E3 ligases. To achieve this goal, we have formulated a multi-disciplinary research team with divere expertise ranging from cancer biology, computer-based in slical screening, medicinal chemistry and X-Ray crystallography study. Using such a approach, we have identified a Skp2 small molecule inhibitor displaying potent anti-tumor acitivty in vivo (Cell, 2013). With suhc an initiative, we hope to develop small molecule inhibitors targeting diverse E3 ligases and others for cancer therapy.

Selected publications:

1.       Jin G., Lee S.W., Zhang X., Cai Z., Gao Y., Chou P.H., Rezaeian A.H., Han F., Wang C.Y., Yao J.C., Gong Z., Chan C.H., Huang C.Y., Tsai F.J., Tsai C.H., Tu S.H., Wu C.H., Sarbassov D., Ho Y.S., Lin H.K. Skp2-mediated RagA ubiquitination elicits a negative feedback to prevent amino-acid-depedent mTORC1 hyperactivation by recruiting GATOR1. Mol. Cell. 2015 Jun 18;58(6):989-1000. doi: 10.1016/j.molcel.2015.05.010. Epub 2015 Jun 4.

2.       Xu D, Li CF, Zhang X, Gong Z, Jin G, Lee SW, Jin G, Rezaeian AH, Chan CH, Han F, Wang J, Yang WL, Feng ZZ, Chen W, Wu CY, Wang YJ, Chow LP, Zhu XF, Zeng YX, Lin HK. Skp2-MacroH2A1-CDK8 axis orchestrates G2/M transition, polyploidy and tumourigenesis. Nat. Commun. 2015 Mar 30;6:6641. doi: 10.1038/ncomms7641.

3.       Lee SW, Li CF, Jin G, Chan CH, Yang WL, Li BK, Cai Z, Han F, Rezaeian AH, Li HY, Huang HY, Lin HK. Skp2-dependent ubiquitination and activation of LKB1 is essential for cancer cell survival under energy stress. Mol. Cell. 2015 Mar 19;57(6):1022-33. doi: 10.1016/j.molcel.2015.01.015. Epub 2015 Feb 26.

4.       Feng H, Lopez GY, Kim CK, Alvarez A, Duncan CG, Nishikawa R, Nagane M, Su AJ, Auron PE, Hedberg ML, Wang L, Raizer JJ, Kessler JA, Parsa AT, Gao WQ, Kim SH, Minata M, Nakano I, Grandis JR, McLendon RE, Bigner DD, Lin HK, Furnari FB, Cavenee WK, Hu B, Yan H, Cheng SY.   EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis. J. Clin. Invest. 2014 Jul 25. pii: 73093. doi: 10.1172/JCI73093. [Epub ahead of print]

5.       Wang J, Han F, Lee SW, Wu J, Chan CH, Zhang X, Gao Y, Su HK, Feng ZZ, Xu DZ, Lin HK. E3-ligase Skp2 regulates β-catenin expression and maintains hematopoietic stem cell homing. Biochem Biophys Res Commun. 2014 Feb 18. pii: S0006-291X(14)00294-0. doi: 10.1016/j.bbrc.2014.02.042. [Epub ahead of print].

6.       Wagner, K., Alam, H., Dhar, S., Giri, U., Li, N., Wei, Y., Giri, D., Cascone, T., Kim., J.-H., Ye, Y., Multani, A., Chan, C.-H., Erez, B., Saigal, B.,  Chung, J., Lin, HK., Wu, X., Hung, MC, Heymach, J., Lee, M. G.  (2013) KDM2A Activates ERK1/2 via DUSP3’s Epigenetic Repression and Promotes NSCLC, J. Clin. Invest. 123(12):5231-46.

7.       Chan CH, Morrow JK, Li CF, Gao Y, Jin G, Moten A, Stagg, LJ, Ladbury, J, Cai Z, Xu, D, Logothetis, CJ, Hung, MC, Zhang S*, Lin HK*.  Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression (2013). Cell. 154, 556-68. PMID: 23911321.

8.       Yang WL, Jin G, Li CF, Jeong YS, Moten A, Xu D, Feng Z, Chen W, Cai Z, Darnay B, Gu W, Lin HK. Cycles of ubiquitination and deubiquitination critically regulate growth factor-mediated activation of Akt signaling (2013). Science Signaling. 2013 Jan 8;6(257):ra3. doi: 10.1126/scisignal.2003197.

9.       Chen D, Sun Y, Wei Y, Zhang P, Rezaeian A.H, Teruya-Feldstein J, Gupta S, Liang H, Lin HK, Hung MC, Ma L (2012). LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker. Nat. Med. 2012 Oct;18(10):1511-7. doi: 10.1038/nm.2940. Epub 2012 Sep 23.

10.   Chan CH, Li CF, Yang WL, Gao Y, Lee SW, Feng Z, Huang HY, Tsai KC, Flores LG, Shao Y, Hazle JD, Yu D, Wei W, Sarbassov D, Hung MC, Nakayama K, Lin HK (2012). The Skp2-SCF ubiquitin ligase regulates Akt ubiquitination, glycolysis, Herceptin sensitivity and tumorigenesis. Cell. 149:1098-111. PMID: 22632973.

11.   Wu J, Zhang X, Zhang L, Wu CY, Rezaeian AH, Chan CH, Li JM, Wang J, Gao Y, Han F, Jeong YS, Yuan Z, Khanna KK, Jin J, Zeng YX, Lin HK (2012). Skp2 E3 ligase integrates ATM activation and homologous recombination repair by ubiquitinating NBS1. Mol. Cell.11;46(3):351-61. Epub 2012 Mar 29. PMID: 22464731.

12.   Wu J, Lee SW, Zhang X, Han F, Kwan SY, Yuan X, Yang WL, Jeong YS, Rezaeian AH, Gao Y, Zeng YX, Lin HK. Foxo3a transcription factor is a negative regulator of Skp2 and Skp2 SCF complex (2012). Oncogene 2012 Feb 6. doi: 10.1038/onc.2012.26. [Epub ahead of print].

13.   Wang J, Han F, Wu J, Lee SW, Chan CH, Wu CY, Yang WL, Gao Y, Zhang X, Jeong YS, Moten A, Samaniego F, Huang P, Liu Q, Zeng YX, Lin HK (2011). The role of Skp2 in the maintenance of quiescence and self-renewal of hematopoietic stem cells.Blood, 118, 5429-38.

14.   Wu CH, Kang HY, Yang WL, Wu J, Jeong YS, Wang J, Chan CH, Lee SW, Zhang X, Lamothe B, Aejandro D. Campos, Darnay B, Lin HK (2011). The critical role of monoubiquitination of H2AX in H2AX phosphorylation and DNA damage. J. Biol.Chem. 286, 30806-15.

15.   Giorgi C, Ito K, Lin HK, Santangelo C, Bersadi R, Rizzuto R, Tacchetti C, Pinton P, Pandolfi PP (2010) Essential role of PML in the regulation of Ca2+-depedent apoptosis at endoplasmic reticulum-mitochondria contact sites. Science, 330, 1247-1251.

16.   Chan CH, Lee SW, Li CF, Wang J, Yang WL, Wu CY, Wu J, Nakayama KI, Kang HY, Huang HY, Hung MC, Pandolfi PP, Lin HK (2010). Deciphering the transcription complex critical for RhoA gene expression and cancer metastasis. Nat. Cell Biol. 12, 457-467.

17.   Yang WL, Wang J, Chan CH, Lee SW, Campos AD, Lamothe B, Hur L, Grabiner B, Lin X, Darnay B, Lin HK (2009). The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science. 325, 1134-1138.

18.   Lin HK, Chen Z, Wang G, Lee SW, Wang J, Chan CH, Yang WL, Nakayama KI, Cordon-Cardo C, Teruya-Feldstein J, Pandolfi PP (2010) Skp2 targeting suppresses tumorigenesis by Arf-p53-indepedent cellular senescence. Nature (Article), 464, 374-379.

19.   Lin HK*, Wang G, Chen Z, Teruya-Feldstein J, Liu Y, Chan CH, Yang WL, Erdjument-Bromage H, Nimer S, Tempst P, Pandolfi PP* (2009) Phosphorylation-dependent regulation of the SCF complex formation and Skp2 oncogenic function by Akt/PKB. Nat. Cell Biol.11, 420-432. *Co-Corresponding author.

20.   Chen Z, Trotman LC, Dotan ZA, Lin HK, Niki M, Koutcher JA, Ludwig T, Cordon-Cardo, C, Pandolfi PP (2005) Critical role of p53 dependent cellular senescence in suppression of Pten deficient tumourigenesis. Nature. 436, 725-730.

21.  Lin HK, Bergmann S, Pandolfi PP (2004) Cytoplasmic PML function in TGF-β signaling.  Nature. 431, 205- 211. 

Full publications can be seen from PubMed:

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