Sudhakar JHA

Follow:

Principal Investigator, Cancer Science Institute of Singapore, NUS
Assistant Professor, Department of Biochemistry, Yong Loo Lin School of Medicine, NUS

csisjha[at]nus.edu.sg

Cancer is recognized conventionally as a genetic disease, caused by changes in the sequence of DNA (mutations). However, recent research highlights the critical role played by epigenetic factors in regulating tumor formation and progression. Epigenetic changes are those which result in alteration of gene expression but are not reflected in the DNA sequence, instead influence how the cells read the information contained in the DNA. My group is interested in studying epigenetic changes and their role in tumorigenesis.

Research

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.