Laboratory of John Hagan, Ph.D.

OVERVIEW

Research in the Hagan laboratory is focused on understanding the roles of 3’ RNA uridylation in regulating gene expression (both microRNAs and mRNAs) and translating these discoveries into novel cancer therapeutics. Our microRNA work revolves primarily around the LIN28/let-7 pathway that plays critical roles in cancer, glucose metabolism, tissue repair, and reprogramming (i.e. the generation of induced pluripotent stem cells).

Recently, we showed that the reprogramming factor and oncogene Lin28A recruits the Terminal Uridylyl Transferase (TUTase) Zcchc11 to block the biogenesis of the tumor suppressor let-7 microRNA family. Also, we demonstrated that inhibition of either LIN28A or ZCCHC11 caused the regression of established human tumors in xenograft models. Reactivation of LIN28A/LIN28B is associated with poor prognosis in more than ten cancer types, including glioblastoma multiforme, medulloblastoma, and neuroblastoma.

Our ongoing microRNA research revolves on elucidating modifiers (chemical and genetic) that restore let-7 expression in human cancer cells  on as well as identifying novel cases where microRNA biogenesis is regulated post-transcriptionally.

In the past year, an additional function for the TUTases ZCCHC11 and ZCCHC6 was reported by Narry Kim’s lab. Specifically, they showed that these enzymes uridylate many polyadenylated mRNAs, resulting in their enhanced degradation. This observation is consistent with our unpublished data where we found that many tumor suppressor genes are regulated negatively by Zcchc11, independently of the Lin28/let-7 pathway.

The clinical significance of this finding is illustrated by the fact that ZCCHC11 and E2F1are a dual gene classifier that predicts poor breast cancer prognosis, independently of tumor subtype and LIN28 status. Therefore, we seek to define specific and cancer relevant changes in gene expression upon modulations of ZCCHC11 levels and understand how mechanistically some mRNA are specifically targeted by 3’ RNA uridylation.

About John Hagan, Ph.D.


CURRENT PROJECTS

1) Determine if the oncogene LIN28B requires a TUTase (e.g. ZCCHC6/TUT7) to repress let-7 microRNA biogenesis

2) Develop small molecule inhibitors of the LIN28 and/or TUTases that restore expression of the tumor suppressor let-7 microRNAs in human cancer cells

3) Interrogate the in vivo functions of TUTases in mammalian development and cancer using mouse models

4) Define how the TUTase Zcchc11 contributes to poor prognosis in breast cancer using both loss- and gain-of-function approaches

5) Determine mechanistically why some mRNAs are targeted by 3’ RNA uridylation while others are not

6) Elucidate novel examples of post-transcriptional regulation of microRNA biogenesis


TEAM MEMBERS

Julien Balzeau, Ph.D., Research Fellow
Miriam Menezes, Ph.D., Research Fellow


RECENT PUBLICATIONS

  1. Cui, X., Zhang, Y., Yang, J., Sun, X., Hagan, J.P., Guha, S., and Li, M. (2014) ZIP4 confers resistance to zinc deficiency-induced apoptosis in pancreatic cancer. Cell Cycle 13(7): 1180-1196 PMID: 24553114
  2. Zhang, Y., Yang, J., Cui, X., Chen, Y., Zhu, V.F., Hagan, J.P., Wang, H., Yu, X., Hodges, S.E., Fang, J., Chiao, P.J., Logsdon, C.D., Fisher, W.E., Brunicardi, F.C., Chen, C., Yao, Q., Fernandez-Zapico, M.E., and Li. M. (2013) A novel epigenetic CREB-miR-373 axis mediates ZIP4-induced pancreatic cancer growth. EMBO Molecular Medicine 5:1322-1334 PMCID: PMC3799489
  3. Shinoda, G., Shyh-Chang, N., de Soysa, T.Y., Zhu, H., Seligson, M.T., Shah, S.P., Abo-Sido, N., Yabuuchi, A., Hagan, J.P., Gregory, R.I., Asara, J.M., Cantley, L.C., Moss, E.G., and Daley, G.Q. (2013) Fetal deficiency of Lin28 programs life-long aberrations in growth and glucose metabolism. Stem Cells 31:1563-1573 PMCID: PMC3775935
  4. Chen, L., Zhang, Y., Yang, J., Hagan, J.P., and Li, M. (2013) Vertebrate Animal Models of Glioma: Understanding the Mechanisms and Developing New Therapies.  Biochimica et Biophysica Acta-Reviews on Cancer doi: 10.1016/j.bbcan.2013.04.003 PMCID: PMC372903
  5. Shinoda, G., de Soysa, T.Y., Seligson, M.T., Yabuuchi, A., Fujiwara, Y., Huang, P.Y., Hagan, J.P., Gregory, R.I., Moss, E.G., and Daley, G.Q. (2013) Lin28a regulates germ cell pool size and fertility.  Stem Cells 31:1001-1009 PMCID: PMC3652309
  6. Abdeen, S.K., Del Mare, S., Hussain, S., Remaileh, M.A., Salah, Z., Hagan, J., Rawahneh, M., Pu, X.A., Russell, S., Stein, J.L., Stein, G.S., Lian, J.B.,  and Aqeilan, R.I. (2013) Conditional inactivation of the mouse WWOX tumor suppressor gene recapitulates the null phenotype.  Journal of Cellular Physiology 228:1377-1382 PMID: 23254685
  7. Chang, H.M., Martinez, N.J., Thornton, J.E., Hagan, J.P., Nguyen, K.D., and Gregory, R.I. (2012) Trim71 cooperates with microRNAs to repress Cdkn1a expression and promote embryonic stem cell proliferation.  Nature Communications 3: 923 PMCID: PMC3518406
  8. Piskounova, E., Polytarchou, C., Thornton, J.E., LaPierre, R.J., Pothoulakis, C., Hagan, J. P., Iliopoulos, D., and Gregory, R.I. (2011) Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms.  Cell 147: 1066-1079. PMCID: PMC3227872
  9. Zhu, H., Shyh-Chang, N., Segrè, A.V., Shinoda, G., Shah, S.P., Einhorn, W.S., Takeuchi, A., Engreitz, J.M, Hagan, J.P., Kharas, M.G., Urbach, A., Thornton, J.E., Triboulet, R., Gregory, R.I., DIAGRAM Consortium, MAGIC Investigators, Altshuler, D., and Daley, G.Q. (2011) The Lin28/let-7 axis regulates glucose metabolism.  Cell 147: 81-94. PMCID: PMC3353524
  10. Motiwala, T., Zanesi, N., Datta, J., Roy, S., Kutay, H., Checovich, A.M., Kaou, M., Zhong, Y., Johnson, A.J., Lucas, D.M., Heerema, N.A., Hagan, J., Mo, X., Jarjoura, D., Byrd, J.C., Croce, C.M., and Jacob. S.T. (2011) AP-1 elements and TCL1 protein regulate expression of the gene encoding protein tyrosine phosphatase PTPROt in leukemia.  Blood 118: 6132-6140 PMCID: PMC3234669