- Ph.D. – The Chinese University of Hong Kong, 2001
- Postdoctoral Fellowship – University of Massachusetts Medical School (research focused on the contribution of estrogen receptor beta to prostate cancer)
Endocrine disruption and human diseases – Endocrine disruptors (EDCs) are ubiquitous and can modify disease risk. But the underlying mechanism remains largely unknown and it is unclear how EDCs interfere with our endocrine systems. Using transcriptomic change as an endpoint, we showed that an environmental estrogen prototype, Bisphenol A (BPA) does not follow a classical toxicological dose-response relationship (i.e. higher dose results in greater response). We are currently studying the endocrine-disrupting effects of metals (including lead and arsenic) and determine their underlying epigenetic changes in an intergeneration animal model.
Epigenetic gene regulation and biomarkers – Genes are regulated by epigenetics, a mechanism that involves DNA methylation, microRNA expression, or histone tail modification. However, it is unclear how epigenetics coordinates with other transcription factors or chromatin remodeling factors in regulating gene expression. Our laboratory is working to uncover the upstream signals that regulate epigenetics and dissect the relationship between DNA methylation and cis-acting elements during transcription. Our lab found that this particular epigenetic mechanism is highly susceptible to environmental insults. Once altered by environmental exposure, many of the molecular changes are stable throughout life, making them excellent biomarkers for monitoring exposures and/or for assessing the underlying disease susceptibility associated with exposures.
Hormone signaling in cancers – The etiology of prostate cancer is still largely unknown. My research team has been exploring mechanisms by which prostate cancer develops and progresses into an aggressive cancer type. We specifically found that cancer cells hijack the hormone receptor pathway to gain growth benefits. One of the latest members of the estrogen receptor (ER) family is called G-protein-coupled estrogen receptor (GPR30 or GPER). Unlike traditional nuclear estrogen receptors ERalpha or ERbeta, GPER is a membrane receptor going through extra-nuclear signaling. Our laboratory recently observed that this receptor was highly expressed in castration-resistant prostate cancer cells and is dissecting its upstream androgen receptor signaling using in vitro and in vivo models.
Genome-wide genomics analysis – Instead of focusing on one-gene one-target approach and finding out potential targets based on published data, our laboratory employ multiple genome-wide approaches to identify key players involved in each experiment. In particular, we used microarray, PCR array and next-generation sequencing to uncover major signaling network changes induced by environmental toxicants or therapeutic drugs in cancers. Currently, we are using single-cell RNA sequencing methods to study the effects of environmental toxicant on several novel subpopulations of prostate stem cells and conducting direct RNA sequencing techniques using nanopore-based platform to identify the change of epitranscriptomics upon environmental exposure.
Recent Research Support
- NIH/NIEHS R01ES032675 (co-Principal Investigator) 4/29/2022-4/28/2027
“RNA modifications by paternal exposure to arsenic and intergenerational effects on sperm quality”
- VA BLRD Merit Award I01BX005395 (Co-Investigator) 10/01/20 – 09/30/24
“Metal-induced cell-level changes in prostate epithelium and cancer risk”
- DOD Investigator-Initiated Research Award W81XWH2210152 (Co-Investigator) 5/1/2022-4/30/2026
“DNA methylation markers associated with exposure and adverse health outcomes in Veterans exposed to airborne hazards from open burn pits”
- Zhang, L., Moccia, M., Briggs, D.C., Bharate, J., Lakkaniga, N.R., Knowles, P.P., Yan, W., Tran, P., Kharbanda, A., Leung, Y.K., Frett, B., Santoro, M., McDonald, N.Q., Carlomagno, F., Li, H.Y. (2022) Discovery of N-trisubstituted Pyrimidine Derivatives as Type-I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose, Journal of Medicinal Chemistry, 65(2):1536-1551. PMID: 35081714
- McDermott, A., Kim, K., Kasper, S., Ho, S.M. and Leung, Y.K. (2022) The androgen receptor inhibits GPER1 by preventing both Sp1 and Sp3 from initiating transcription in prostate cancer cells, Oncotarget, 13:46-60. PMID: 35018219 PMCID: PMC8741193
- Ho, S.M., Rao, R., Ouyang, B., Tam, N., Schoch, E., Song, D., Ying, J., Leung, Y.K., Govindarajah, V., Tarapore, P. (2021) Three generation study in male rats gestationally exposed to high butter fats and bisphenol A: impaired spermatogenesis, penetrance with reduced severity, Nutrients, 13: 3636. PMID: 34684636
- Zhang, L., Lakkaniga, N., Bharate, J., Mcconnell, N., Wang, X., Kharbanda, A., Leung, Y.K., Frett, B., Shah, N., Li, H.Y. (2021) Discovery of imidazo[1,2-a]pyridine-thiophene derivatives as FLT3 and FLT3 mutants inhibitors for acute myeloid leukemia through structure based optimization of an NEK2 inhibitor, European Journal of Medicinal Chemistry, 225:113776. PMID: 34479037
- Kharbanda, A., Tran, P., Zhang, L., Leung, Y.K., Li, H.Y. (2021) Discovery of 4-aminoquinolines as highly selective TGFβR1 inhibitors with an attenuated MAP4K4 profile for potential applications in immune-oncology, European Journal of Medicinal Chemistry, 225:113763. PMID:34419892
- Kharbanda, A., Zhang, L., Saha, D., Tran, P., Xu, K., Li M.O., Leung, Y. K., Frett, B., Li, H.Y. (2021) Discovery and biological evaluation of phthalazines as novel non-kinase TGFβ pathway inhibitors, European Journal of Medicinal Chemistry, 223:113660. PMID: 34246853
- Padala, K.P., Padala, P.R., Leung, Y.K., Dennis, R.A., Ho, S.M. (2021) Untangling the Complex Interactions of Open Burn Pit Exposure and Health Outcomes: Response to Brumage et al, The Primary Care Companion for CNS disorders, 23:02796. PMID: 34000124
- *Leung, Y.K., Biesiada, J., Govindarajah, V., Ying, J., Kendler, A., Medvedovic, M., *Ho, S.M. (2020) Low-Dose Bisphenol A in a Rat Model of Endometrial Cancer: A CLARITY-BPA Study, Environmental Health Perspectives, 128:127005. PMID: 33296240
- Padala. K.P., Padala, P.R., Leung, Y.K., Dennis, R.A., Ho, S.M. (2020) Open Burn Pit Exposure and Concern about the COVID-19 Pandemic. The Primary Care Companion for CNS disorders, 22:02796. PMID: 33166097