Integrative Approach to Targeting Chromatin Remodeling in Breast Cancer Therapy
- Author(s): Mollah, Shamim
- Advisor(s): Subramaniam, Shankar
- et al.
With the advent of high-throughput technologies, large-scale multi-omics data integration approaches have revolutionized our understanding of cancer and its progression. In this dissertation, we focus on deciphering the molecular mechanisms of various targeted cancer treatments and growth factors on chromatin remodeling through integrative analyses of multi-omics data. Chromatin remodeling is involved in the stability of genome structure, gene expression, and DNA repair, as well as, cell growth and progression; therefore, it plays an essential role in tumor suppression. The regulation of chromatin remodeling is carried out by the precise coordination of covalent histone modifications and remodeler proteins through catalytic activities. Disruption of these regulated activities confers a unique ability for healthy cells to reprogram their genome for the maintenance of oncogenic phenotypes. Hence, these histone modifications and remodeler proteins are potential targets for cancer treatments. While many drugs have the potential to target histone modifications and remodeler proteins, their precise mechanisms of action, i.e., alterations in cellular reprogramming, are not well studied. To address this gap, we utilized latent space models to integrate multi-omics data such as proteomic/phosphoproteomic, transcriptomic, and epigenomic data to understand the effects of various drugs and growth factors on specific genes, proteins, and phosphoproteins that are involved in the regulation of a wide range of cellular processes (growth, proliferation, and cell division) and gene activity states in cancer and healthy cell lines. In addition to providing mechanistically-driven targets that can impact chromatin remodeling, the chromatin fingerprints generated from our study can serve as a signature for assessing the efficacy of a given drug in treating cancer. Further, increasing evidence, supported by our study of breast cancer, indicates that this paradigm applies to various cancers, and further analysis can provide insights into more detailed chromatin-based mechanisms. Our study implies that the cancer state is one where chromatin gets remodeled, and effective drugs attempt to restore the chromatin state to that of a healthy cell. Overall, the integrative frameworks we developed reveal the mechanisms of action of specific drugs on chromatin remodeling machinery in breast cancer cells and of growth factors on cellular phenotypes in normal breast cells, which lay the foundation for improved development of chromatin-based cancer therapy.