Witcher Lab members (left – right): Dr. Yuan Jiang (research assistant),Dr. Tiejun Zhao (senior research assistant),
Benjamin LeBeau (graduate student),Dr. Michael Witcher (principal investigator), Tatiana Shorstova (graduate student),
Maika Jangal (postdoctoral fellow), Su Jie (animal care specialist), Eduardo CepedaCanedo (graduate student).
General Overview of Our Research:
Epigenetics is defined as molecular factors that regulate regulate genome activity, independently of DNA sequence. This includes histone modification, DNA methylation and non-coding RNAs. In our lab we study epigenetic defects in Breast and Ovarian Cancers. Through understanding how such aberrations give rise to cancer, we can gain critical insights allowing us to develop new therapeutic approaches to treat these diseases.
We incorporate both classical and cutting edge technologies to examine genome wide epigenetic reprogramming in cancer and develop new small molecule inhibitors targeting epigenetic processes. These techniques include, Chromatin-IP, ChIP-seq, RNA-seq, laser micro-irradiation, Mass Spectrometry, CRISPR-Cas9, and animal models of cancer.
||We think that cancer cells develop a signaling network connecting the micro-environment to chromatin regulators, resulting in epigenetic reprogramming.
Specific Projects in the lab
1. Understanding the consequences of CTCF dysfunction in cancer
CTCF is a multi-functional, master- regulator of the human genome. It may be functionally inactivated in cancer via several mechanisms including; 1) Deletion 2) Mutation3) loss of the post-translational modification poly (ADP-ribosylation) 4) Mutation of its DNA binding sites.
We aim to explore the epigenetic and transcriptional consequences of these defects. Unexpectedly, we have established a new role for CTCF in the repair of double strand breaks. We are now exploring whether this novel function of CTCF is disrupted in cancer, and promotes oncogenic progression.
The transcription factor TFII-I targets CTCF to metabolism-related genes.
Results of ChIP-seq experiments.
2. Drugging the epigenome as an approach to fight ovarian cancer.
Using RNA-seq and Chromatin-IP, we have uncovered epigenetic defects which are enabling us to find new therapeutic avenues to treat untreatable cancers.
|| RNA-seq data from Ovarian cancer cell lines treated with drugs targeting the epigenome.
3. Targeting poly (ADP-ribosylation)
Poly (ADP-ribosylation) is a protein modification placed by PARP-1. We have evidence that this pathway is abnormal in a spectrum of cancers. By targeting this pathway through unique means developed by my lab, we are able to either promote, or effectively slow, the growth of primary and metastatic breast cancers.
||Ablation of lung metastases by manipulating the poly(ADP-ribose) pathway.
||Triple-negative Breast Cancer cells reprogrammed to acquire more physiological, epithelial-like characteristics after modulation of the poly (ADP-ribose) pathway.
Witcher Lab publications:
(* denotes corresponding authorship)
1. Oncogenic activity of Poly (ADP-ribose) glycohydrolase
Maud Marques, Maika Jangal, Wang LC, Amanda Lovato, Tiejun Zhao, Su Jie, Sonia del Rincon, Moulay Alaoui-Jamai, and Michael Witcher*
2. Compromised expression of Swi/Snf catalytic subunits predict sensitivity to bromodomain inhibitors
Tatiana Shorstova, Maud Marques, Jie Su, Jake Johnston, Claudia L. Kleinman, Nancy Hamel, Sidong Huang, Moulay A. Alaoui-Jamali, William D. Foulkes and Michael Witcher*
3. Tang L, Morris J, Wan J, Moore C, Fujita Y, Gillaspie S, Aube E, Nanda J, Marques M, Jangal M, Anderson A, Cox C, Hiraishi H, Dong L, Saito H, Singh CR, Witcher M, Topisirovic I, Qian SB, Asano K.
Competition between translation initiation factor eIF5 and its mimic protein 5MP determines non-AUG initiation rate genome-wide.
Nucleic Acids Res. 2017 Sep 18. doi: 10.1093/nar/gkx808
4. Hilmi K, Jangal M, Marques M, Zhao T, Saad S, Zhang C, Luo VM, Syme A, Rejon C, Yu Z, Krum A, Fabian MR, Richard S, Alaoui-Jamali M, Orthwein A, McCaffrey L and Witcher M*.
CTCF facilitates DNA double-strand break repair by enhancing homologous recombination repair.
Science Advances (AAAS, Science). 2017 May 24;3(5):e1601898.
5. Saad A, Bijian K, Qiu D, da Silva SD, Marques M, Chang CH, Nassour H, Ramotar D, Damaraju S, Mackey J, Bismar T, Witcher M, Alaoui-Jamali MA.
Insights into a novel nuclear function for Fascin in the regulation of the amino-acid transporter SLC3A2.
Sci Rep. 2016 Nov 7;6:36699.
6. Kazanets A, Shorstova T, Hilmi H, Marques M, and Witcher M*
Epigenetic silencing of tumro suppressor genes: Paradigms, Puzzles and potential.
BBA Reviews Cancer. 2016 Apr;1865(2):275-88.
7. Manteghi S, Gingras MC, Kharitidi D, Galarneau L, Yan M, Marques M, Robert F, Cencic R, Paquet M, Witcher M, Pelletier M and Pause A.
Haploinsufficiency of the ESCRT component HD-PTP predisposes to cancer.
Cell Rep. 2016 May 18. pii: S2211-1247(16)30520-4.
8. Marques M, Beauchamp MC, Laskov I, Qiang S, Gotlieb WH and Witcher M*
Chemotherapy depletes PARP1 protein in ovarian cancer tumors: Implications for future clinical trials involving PARP inhibitors.
BMC Medicine. 2015 Sep 9;13(1):217. doi: 10.1186/s12916-015-0454-9.
9. Peña-Hernández R, Marques M, Hilmi K, Zhao T, Saad A, Alaoui-Jamali MA, Del Rincon SV, Ashworth T, Roy AL, Emerson BM, Witcher M*
Genome-wide targeting of the epigenetic regulatory protein CTCF to gene promoters by the transcription factor TFII-I.
Proc Natl Acad Sci U S A. 2015 Feb 17;112(7):E677-86.
10. Anti-cancer properties of Phyllanthus emblica (Indian Gooseberry)
Zhao T, Sun Q, Marques M and Witcher M*
Oxidative Medicine and Cellular Longevity. 2015; 950890.
11. Marques M, Hernandez R and Witcher M*
Genome wide analysis of the role of the general transcription factor TFII-I in regulating gene expression and targeting CTCF binding to gene promoters.
Genomics Data, Volume 4, June 2015, Pages 17–21
12. Zhao T, Sun Q, del Rincon SV, Lovato A, Marques M and Witcher M*
Gallotannin imposes S phase arrest in breast cancer cells and suppresses the growth of triple-negative tumors in vivo.
PLoS One. 2014 Mar 21;9(3):e92853. doi: 10.1371/journal.pone.0092853.
13. Lovato A, Panaschi L, Witcher M*
Is there an epigenetic component underlying the resistance of triple-negative breast cancers to Parp inhibitors?
Frontiers in Pharmacology of anti-cancer drugs. 2012;3:202.
14. Balakrishnan SK, Witcher M, Berggren TW, Emerson BM.
Functional and Molecular Characterization of the Role of CTCF in Human Embryonic Stem Cell Biology.
PLoS One. 2012;7(8):e42424.
15. DiTacchio L, Le HD, Vollmers C, Hatori M, Witcher M, Secombe J, Panda S.
Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences the circadian clock.
Science. 2011 Sep 30;333(6051):1881-5.
16. Witcher M and Emerson BM
Epigenetic Silencing of the p16INK4a Tumor Suppressor is Associated with Loss of CTCF Binding and a Chromatin Boundary.
Molecular Cell 2009 May 15; 34(3): 271- 84