My group is interested in understanding the regulation of chromatin-remodeling complexes and their role in cancer prevention and intervention (Molecular Cell 2009, 34: 521-533). During our quest to identify epigenetic regulators downregulated in cancers, we found TIP60’s stability to be compromised by viruses, such as human papillomavirus (HPV) (Molecular Cell 2010, 38: 700-711), adenovirus (AdV) (Oncogene 2013, 32: 5017-25) and hepatitis B virus (HBV) (Hora et al. 2020, manuscript submitted). By using both in vitro and in vivo model systems, we also established that these viruses target TIP60 to accelerate the process of oncogenesis by hijacking cellular pathways that promote growth (Oncogene 2016, 35: 2062-74 and PLoS Pathog 2017, 18;13(10): e1006681). Most importantly, we discovered the cellular E3 ligase (EDD1) that viruses like HPV use to prime TIP60’s degradation (Oncogene 2016, 35: 2062-74). In addition to virus-induced cancers, this chromatin remodeler is also known to be downregulated in breast and colorectal cancers. Interestingly, this regulation is not at the protein level, which intrigued us and led to the investigation of other possible mechanisms of gene regulation. To our surprise, we found an oncogenic microRNA (miR-22) to target 3’UTR of TIP60, and downregulate it in breast cancer (Oncotarget 2015, 6: 41290-306). Additionally, we showed that by targeting TIP60, miR-22 stimulates an epithelial-mesenchymal transition (EMT) program by activation of the SNAIL2-DNMT1 pathway (J Mol Cell Bio 2016, 8: 384–399). In the case of colorectal cancer, we identified the role of TIP60 in the silencing of endogenous retroviral elements (ERVs). Importantly, we discovered that TIP60-depleted colorectal cancer cells are sensitive to reverse transcriptase (RT) inhibitors (Nucleic Acids Res. 2018, 46:9456-9470). Moving forward, we plan to advance the epigenetic platforms and models that my group has developed to enable new therapeutics for cancers.

1. circASXL1-1 regulates BAP1 deubiquitinase activity in leukemia. Jadhav S, Kumari N, Ng L, Tan PF, Yeo-The NSL, Tian JS, Koh BTH, Chan MC, Wong W, Chng WJ, Fullwood MJ, Guccione E, Karnani N, Tenen DG and Jha S. Haematologica. 2020 Jul;105(7):e343-e348.

2. TIP60 represses activation of endogenous retroviral elements. Rajagopalan D, Magallanes RT, Bhatia SS, Sian S, Hora S, Lee KK, Zhang Y, Jadhav SP, Wu Y, Gan Y, Karnani N, Benoukraf T and Jha S. Nucleic Acids Res. 2018 Oct 12;46(18):9456-9470. (Highlight: “Faculty of 1000 Biology”, 31^st July 2018) (https://f1000.com/prime/article?articleId=733701718&target=/prime/733701718&ref=ypp)

3. High-Risk Human Papillomaviral Oncogenes E6 and E7 Target Key Cellular Pathways to Achieve Oncogenesis. Yeo-Teh NSL, Ito Y, Jha S. Int J Mol Sci. 2018 Jun 8;19(6). pii: E1706.

4. An epi(c)genetic war: Pathogens, Cancer and the Human Genome. Rajagopalan D and Jha S. BBA Reviews on Cancer, 2018 Apr;1869(2):333-345.

5. TIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter. Rajagopalan D, Pandey AK, Xiuzhen MC, Lee KK, Hora S, Zhang Y, Chua BH, Kwok HS, Bhatia SS, Deng LW, Tenen DG, Kappei D and Jha S. PLoS Pathog. 2017 Oct 18;13(10): e1006681.

6. TIP60 inhibits metastasis by ablating DNMT1-Snail2 driven epithelial-mesenchymal transition program. Zhang Y, Subbaiah VK, Rajagopalan D, Tham CY, Abdullah LN, Toh TB, Gong M, Tan TZ, Jadhav SP, Pandey AK, Karnani N, Chow EK, Thiery JP and Jha S.J Mol Cell Biol 2016 Oct; 8(5), 384–399. (Editorial highlight: “New factors involved in tumorigenesis”.) (http://jmcb.oxfordjournals.org/content/8/5/371.full.pdf+html)

7. E3 ligase EDD1/UBR5 is utilized by the HPV E6 oncogene to destabilize tumor suppressor TIP60. Subbaiah VK, Zhang Y, Rajagopalan D, Abdullah LN, Yeo-Teh NS, Tomai? V, Banks L, Myers MP, Chow EK, Jha S. Oncogene. 2016 Apr 21;35(16):2062-74.

8. TIP60-miR-22 axis as a prognostic marker of breast cancer progression. Pandey AK, Zhang Y, Zhang S, Li Y, Tucker-Kellogg G, Yang H, Jha S. Oncotarget. 2015 Dec 1;6(38):41290-306.

9. Destabilization of TIP60 by human papillomavirus E6 results in attenuation of TIP60-dependent transcriptional regulation and apoptotic pathway. Jha S, Vande Pol S, Banerjee NS, Dutta AB, Chow LT, Dutta A. Mol Cell. 2010 Jun 11;38(5):700-11. (Highlight: “Faculty of 1000 Biology”, 17^th June 2010) (https://f1000.com/prime/3594975#recommendations-content)

10. RVB1/RVB2: running rings around molecular biology. Jha S, Dutta A. Mol Cell. 2009 Jun 12;34(5):521-33.