Cancer cells are heterogeneous, and the existence of different subpopulations each with potentially distinct biological behaviors adds new layers of complexity for mechanistic studies. Moreover, recognizing the nature of cancer as a constantly adapting “organism” implies that its diverse mechanisms of action is also capable of evolving. This dissertation employs arsenic as the focal carcinogen because it acts through multiple pathways in eliciting human cancers, making it an ideal model to study the equally complex mechanisms of carcinogenesis. Specifically, this dissertation examines two epigenetic mechanisms of action: 1) induction of canonical histone H3.1 mRNA polyadenylation through Stem-Loop Binding Protein (SLBP) degradation and 2) microRNA-31 regulation of Special AT-rich Sequence-Binding protein2 (SATB2).
In the first study, I set out to examine the functional relevance of canonical histone H3.1 mRNA polyadenylation (poly(A)) in malignant cell transformation in vitro and tumor formation in vivo. Results indicate that ectopic H3.1 poly(A) expression in human bronchial epithelial (BEAS-2B) cells is capable of promoting cell proliferation and anchorage-independent growth. In addition, in vivo tumor-forming abilities were examined through subcutaneous injection of H3.1 poly(A)-transfected cells in athymic nude mice xenograft models. Furthermore, stable overexpression of SLBP revealed an inverse relationship with H3.1 polyadenylation and a protective role against arsenic-induced cell transformation.
The second study centers around the regulation of SATB2, a transcription factor and nuclear matrix attachment region-binding protein, via miR-31 down-regulation. MiR-31 is able to bind SATB2 mRNA at two non-coding sequence sites in the 3’UTR and post-transcriptionally inhibit its mRNA translation. Results showed that the inhibitory effect of miR-31 is disrupted in
BEAS-2B cells after arsenic exposure leading to the upregulation of SATB2 protein and subsequent increase in cell proliferation, invasion, and anchorage-independent growth.
The third study employs genome-wide gene expression analysis of peripheral blood mononuclear cells (PBMCs) from Bangladeshi participants chronically exposed to arsenic-contaminated drinking water. The analysis was performed using RNA Sequencing (RNA-Seq) analysis, and the 29 female participants were recruited as a part of the Health Effects of Arsenic Longitudinal Study (HEALS) cohort. Results revealed that 1,054 genes were significantly altered with increasing urinary arsenic levels. Prominent cancer genes in this list include Early growth response protein 2 (EGR2), Zinc finger 516 (ZNF516), Death associated protein kinase 1 (DAPK1), and Tumor necrosis factor alpha induced protein 2 (TNFAIP2). In addition, associated networks and molecular pathways detected based on Ingenuity Pathway Analysis include RNA post-translational modification, damage, and repair, as well as cellular assembly and organization.
|Advisor:||Costa, Max, Klein, Catherine|
|Commitee:||Jin, Chunyuan, Shen, Steven, Sun, Hong|
|School:||New York University|
|Department:||Environmental Health Science|
|School Location:||United States -- New York|
|Source:||DAI-B 81/2(E), Dissertation Abstracts International|
|Subjects:||Health sciences, Environmental Health, Medicine|
|Keywords:||Carcinogenesis, Epigenetics, Histone variants, Mechanisms, Molecular|
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