Browsing by Author "Parker, Taylor M."

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    Cell competition and tumor heterogeneity
    (Elsevier, 2019) Parker, Taylor M.; Henriques, Vanessa; Beltran, Antonio; Nakshatri, Harikrishna; Gogna, Rajan; Surgery, School of Medicine
    Cancers exhibit a remarkable degree of intratumoral heterogeneity (ITH), which results from complex cellular interactions amongst various cell types. This phenomenon provides an opportunity for clonal selection and growth advantages to aggressive cancer cell types, resulting in worse prognosis and challenges to anti-cancer therapy. Cell competition is a conserved mechanism operational in cellular and organ systems, which allows neighboring cells to compare their relative fitness levels and results in the elimination of viable but suboptimal cells. By abuse of this conserved homeostasis mechanism, aggressive cancer cell types gain an advantage over normal cell types by achieving traits like increased proliferation, de-differentiation, and stemness. This review presents recent evidence that cell competition mechanisms actively participate in the regulation of intratumoral cell-cell interactions and thus contribute to ITH, and this process is essential for cancer development and progression.
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    The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53
    (American Society for Biochemistry and Molecular Biology, 2018-03-23) Madan, Esha; Parker, Taylor M.; Bauer, Matthias R.; Dhiman, Alisha; Pelham, Christopher J.; Nagane, Masaki; Kuppusamy, M. Lakshmi; Holmes, Matti; Holmes, Thomas R.; Shaik, Kranti; Shee, Kevin; Kiparoidze, Salome; Smith, Sean D.; Park, Yu-Soon A.; Gomm, Jennifer J.; Jones, Louise J.; Tomás, Ana R.; Cunha, Ana C.; Selvendiran, Karuppaiyah; Hansen, Laura A.; Fersht, Alan R.; Hideg, Kálmán; Gogna, Rajan; Kuppusamy, Periannan; Surgery, School of Medicine
    p53 is an important tumor-suppressor protein that is mutated in more than 50% of cancers. Strategies for restoring normal p53 function are complicated by the oncogenic properties of mutant p53 and have not met with clinical success. To counteract mutant p53 activity, a variety of drugs with the potential to reconvert mutant p53 to an active wildtype form have been developed. However, these drugs are associated with various negative effects such as cellular toxicity, nonspecific binding to other proteins, and inability to induce a wildtype p53 response in cancer tissue. Here, we report on the effects of a curcumin analog, HO-3867, on p53 activity in cancer cells from different origins. We found that HO-3867 covalently binds to mutant p53, initiates a wildtype p53-like anticancer genetic response, is exclusively cytotoxic toward cancer cells, and exhibits high anticancer efficacy in tumor models. In conclusion, HO-3867 is a p53 mutant-reactivating drug with high clinical anticancer potential.
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    HIF-transcribed p53 chaperones HIF-1α
    (Oxford University Press, 2019-11-04) Madan, Esha; Parker, Taylor M.; Pelham, Christopher J.; Palma, Antonio M.; Peixoto, Maria L.; Nagane, Masaki; Chandaria, Aliya; Tomás, Ana R.; Canas-Marques, Rita; Henriques, Vanessa; Galzerano, Antonio; Cabral-Teixeira, Joaquim; Selvendiran, Karuppaiyah; Kuppusamy, Periannan; Carvalho, Carlos; Beltran, Antonio; Moreno, Eduardo; Pati, Uttam K.; Gogna, Rajan; Surgery, School of Medicine
    Chronic hypoxia is associated with a variety of physiological conditions such as rheumatoid arthritis, ischemia/reperfusion injury, stroke, diabetic vasculopathy, epilepsy and cancer. At the molecular level, hypoxia manifests its effects via activation of HIF-dependent transcription. On the other hand, an important transcription factor p53, which controls a myriad of biological functions, is rendered transcriptionally inactive under hypoxic conditions. p53 and HIF-1α are known to share a mysterious relationship and play an ambiguous role in the regulation of hypoxia-induced cellular changes. Here we demonstrate a novel pathway where HIF-1α transcriptionally upregulates both WT and MT p53 by binding to five response elements in p53 promoter. In hypoxic cells, this HIF-1α-induced p53 is transcriptionally inefficient but is abundantly available for protein-protein interactions. Further, both WT and MT p53 proteins bind and chaperone HIF-1α to stabilize its binding at its downstream DNA response elements. This p53-induced chaperoning of HIF-1α increases synthesis of HIF-regulated genes and thus the efficiency of hypoxia-induced molecular changes. This basic biology finding has important implications not only in the design of anti-cancer strategies but also for other physiological conditions where hypoxia results in disease manifestation.
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    Nonlinear relationship between chromatin accessibility and estradiol-regulated gene expression
    (Nature, 2021-02) Chen, Duojiao; Parker, Taylor M.; Bhat-Nakshatri, Poornima; Chu, Xiaona; Liu, Yunlong; Wang, Yue; Nakshatri, Harikrishna; Surgery, School of Medicine
    Chromatin accessibility is central to basal and inducible gene expression. Through ATAC-seq experiments in estrogen receptor-positive (ER+) breast cancer cell line MCF-7 and integration with multi-omics data, we found estradiol (E2) induced chromatin accessibility changes in a small number of breast cancer-relevant E2-regulated genes. As expected, open chromatin regions associated with E2-inducible gene expression showed enrichment of estrogen response element (ERE) and those associated with E2-repressible gene expression were enriched for ERE, PBX1, and PBX3. While a significant number of open chromatin regions showed pioneer factor FOXA1 occupancy in the absence of E2, E2-treatment further enhanced FOXA1 occupancy suggesting that ER–E2 enhances chromatin occupancy of FOXA1 to a subset of E2-regulated genes. Surprisingly, promoters of 80% and enhancers of 60% of E2-inducible genes displayed closed chromatin configuration both in the absence and presence of E2. Integration of ATAC-seq data with ERα ChIP-seq data revealed that ~40% ERα binding sites in the genome are found in chromatin regions that are not accessible as per ATAC-seq. Such ERα binding regions were enriched for binding sites of multiple nuclear receptors including ER, ESRRB, ERRγ, COUP-TFII (NR2F2), RARα, EAR2 as well as traditional pioneer factors FOXA1 and GATA3. Similar data were also obtained when ERα ChIP-seq data were integrated with MNase-seq and DNase-seq data sets. In summation, our results reveal complex mechanisms of ER–E2 interaction with nucleosomes. Notably, “closed chromatin” configuration as defined by ATAC-seq or by other techniques is not necessarily associated with lack of gene expression and technical limitations may preclude ATAC-seq to demonstrate accessibility of chromatin regions that are bound by ERα.