Honors & Awards
T. C. Hsu Memorial Research Scholarship, MD Anderson Cancer Center UT Health Graduate School (2016)
GSBS Endowment in Biochemistry and Molecular Biology Research Award, MD Anderson Cancer Center UT Health Graduate School (2015)
CPRIT - Graduate Scholar, MD Anderson Cancer Center UT Health Graduate School (2015-2016)
Center for Cancer Epigenetics Scholar, MD Anderson Cancer Center UT Health Graduate School (2013-2014)
Doctor of Philosophy, Univ Texas Health Science Ctr-Houston (2016)
M.S., University of Pune, Microbiology (2008)
Amato Giaccia, Postdoctoral Faculty Sponsor
Amato J Giaccia, Todd A Aguilera, Mihalis S Kariolis, Yu Miao, Kaushik Thakkar, Xin Eric Zhang. "United States Patent US20200181231A1 sPD-1 VARIANT-FC FUSION PROTEINS", Akso Biopharmaceutical Inc, Leland Stanford Junior University, Jun 6, 2020
The m6A RNA demethylase FTO is a HIF-independent synthetic lethal partner with the VHL tumor suppressor.
Proceedings of the National Academy of Sciences of the United States of America
Loss of the von Hippel-Lindau (VHL) tumor suppressor is a hallmark feature of renal clear cell carcinoma. VHL inactivation results in the constitutive activation of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2 and their downstream targets, including the proangiogenic factors VEGF and PDGF. However, antiangiogenic agents and HIF-2 inhibitors have limited efficacy in cancer therapy due to the development of resistance. Here we employed an innovative computational platform, Mining of Synthetic Lethals (MiSL), to identify synthetic lethal interactions with the loss of VHL through analysis of primary tumor genomic and transcriptomic data. Using this approach, we identified a synthetic lethal interaction between VHL and the m6A RNA demethylase FTO in renal cell carcinoma. MiSL identified FTO as a synthetic lethal partner of VHL because deletions of FTO are mutually exclusive with VHL loss in pan cancer datasets. Moreover, FTO expression is increased in VHL-deficient ccRCC tumors compared to normal adjacent tissue. Genetic inactivation of FTO using multiple orthogonal approaches revealed that FTO inhibition selectively reduces the growth and survival of VHL-deficient cells in vitro and in vivo. Notably, FTO inhibition reduced the survival of both HIF wild type and HIF-deficient tumors, identifying FTO as an HIF-independent vulnerability of VHL-deficient cancers. Integrated analysis of transcriptome-wide m6A-seq and mRNA-seq analysis identified the glutamine transporter SLC1A5 as an FTO target that promotes metabolic reprogramming and survival of VHL-deficient ccRCC cells. These findings identify FTO as a potential HIF-independent therapeutic target for the treatment of VHL-deficient renal cell carcinoma.
View details for DOI 10.1073/pnas.2000516117
View details for PubMedID 32817424
- Modulating the tumor microenvironment to enhance efficacy of PARP inhibitors AMER SOC CLINICAL ONCOLOGY. 2019
Generation of Stable Expression Mammalian Cell Lines Using Lentivirus.
2018; 8 (21)
Lentiviruses are used very widely to generate stable expression mammalian cell lines. They are used for both gene down-regulation (by using shRNA) or for gene up-regulation (by using ORF of gene of interest). The technique of generating stable cell lines using 3rd generation lentivirus is very robust and it typically takes about 1-2 weeks to get stable expression for most mammalian cell lines. The advantage of using the 3rd generation lentivirus are that are very safe and they are replication incompetent.
View details for PubMedID 30505888
Cross-talk between chromatin acetylation and SUMOylation of tripartite motif-containing protein 24 (TRIM24) impacts cell adhesion.
The Journal of biological chemistry
Proteins with domains that recognize and bind post-translational modifications (PTMs) of histones are collectively termed epigenetic readers. Numerous interactions between specific reader protein domains and histone PTMs and their regulatory outcomes have been reported, but little is known about how reader proteins may in turn be modulated by these interactions. Tripartite motif-containing protein 24 (TRIM24) is a histone reader aberrantly expressed in multiple cancers. Here, our investigation revealed functional crosstalk between histone acetylation and TRIM24 SUMOylation. Binding of TRIM24 to chromatin via its tandem PHD-bromodomain, which recognizes unmethylated lysine 4 and acetylated lysine 23 of histone H3 (H3K4me0/K23ac), led to TRIM24 SUMOylation at lysine residues 723 and 741. Inactivation of the bromodomain, either by mutation or with a small-molecule inhibitor, IACS-9571, abolished TRIM24 SUMOylation. Conversely, inhibition of histone deacetylation markedly increased TRIM24's interaction with chromatin and its SUMOylation. Of note, gene expression profiling of MCF7 cells expressing wild type versus SUMO-deficient TRIM24 identified cell adhesion as the major pathway regulated by the cross-talk between chromatin acetylation and TRIM24 SUMOylation. In conclusion, our findings establish a new link between histone H3 acetylation and SUMOylation of the reader protein TRIM24, a functional connection that may bear on TRIM24's oncogenic function and may inform future studies of PTM cross-talk between histones and epigenetic regulators.
View details for PubMedID 29523690
- Regulation of gene expression in human cancers by TRIM24 Drug Discovery Today: Technologies 2016
Tissue-specific metabolism and TRIM24.
2015; 7 (10): 736-737
View details for PubMedID 26454661
TRIM24 links glucose metabolism with transformation of human mammary epithelial cells
2015; 34 (22): 2836-2845
Tripartite motif 24 protein (TRIM24) is a plant homeodomain/bromodomain histone reader, recently associated with poor overall survival of breast-cancer patients. At a molecular level, TRIM24 is a negative regulator of p53 levels and a co-activator of estrogen receptor. However, the role of TRIM24 in breast tumorigenesis remains largely unknown. We used an isogenic human mammary epithelial cell (HMEC) culture model, derived from reduction mammoplasty tissue, and found that ectopic expression of TRIM24 in immortalized HMECs (TRIM24 iHMECs) greatly increased cellular proliferation and induced malignant transformation. Subcutaneous injection of TRIM24 iHMECs in nude mice led to growth of intermediate to high-grade tumors in 60-70% of mice. Molecular analysis of TRIM24 iHMECs revealed a glycolytic and tricarboxylic acid cycle gene signature, alongside increased glucose uptake and activated aerobic glycolysis. Collectively, these results identify a role for TRIM24 in breast tumorigenesis through reprogramming of glucose metabolism in HMECs, further supporting TRIM24 as a viable therapeutic target in breast cancer.
View details for DOI 10.1038/onc.2014.220
View details for Web of Science ID 000355324300003
View details for PubMedID 25065590
Biological synthesis of metallic nanoparticles
NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE
2010; 6 (2): 257-262
The synthesis of metallic nanoparticles is an active area of academic and, more importantly, "application research" in nanotechnology. A variety of chemical and physical procedures could be used for synthesis of metallic nanoparticles. However, these methods are fraught with many problems including use of toxic solvents, generation of hazardous by-products, and high energy consumption. Accordingly, there is an essential need to develop environmentally benign procedures for synthesis of metallic nanoparticles. A promising approach to achieve this objective is to exploit the array of biological resources in nature. Indeed, over the past several years, plants, algae, fungi, bacteria, and viruses have been used for production of low-cost, energy-efficient, and nontoxic metallic nanoparticles. In this review, we provide an overview of various reports of synthesis of metallic nanoparticles by biological means.This review provides an overview of various methods of synthesis of metallic nanoparticles by biological means. Many chemical and physical procedures used for synthesis of metallic nanoparticles are fraught with major problems: toxic solvents, hazardous by-products, high energy consumption. Over the past several years, plants, algae, fungi, bacteria, and viruses have been used for production of low-cost, energy-efficient, and nontoxic metallic nanoparticles.
View details for DOI 10.1016/j.nano.2009.07.002
View details for Web of Science ID 000276090600007
View details for PubMedID 19616126