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- Pizzolato, Giulia, 1990-
(författare)
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Molecular characterization of FOX factors and Wnt signalling interplay in human cancers
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Wnt/β-catenin signalling, also referred to as canonical Wnt signalling, is a critical regulator of tissue homeostasis and of the differentiation of cells during development. The outcome of canonical Wnt pathway activity is defined by the regulation of target gene transcription, which ultimately determines cell identity and proliferation. How multiple proteins coordinate to modulate Wnt signalling in numerous tissues is an evolving question.Over the years, FOX transcription factors have been emerging as modulators of Wnt signalling in a variety of tissue and cell-specific contexts. Nevertheless, the function of each FOX protein in the pathway as well as their role in different pathophysiological contexts is an open matter.The overall aim of this thesis was to investigate two FOX family members, FOXB2 and FOXQ1, to uncover their roles in Wnt/β-catenin signalling. Additionally, in the last work, I aimed to investigate how the FOXQ1 oncogene is transcriptionally regulated in cancer.In the first paper, we uncovered FOXB2 as a new potent activator of Wnt signalling via the induction of agonistic Wnt ligands, particularly WNT7B. In addition, FOXB2 is induced in aggressive prostate cancer where it is associated with a neuroendocrine differentiation program and poor prognosis.In the second paper, we explored the molecular mechanisms used by the carcinoma oncogene FOXQ1 to drive Wnt signalling activation. Our results showed that FOXQ1 has a major role in tuning the Wnt transcriptional output and, in synergy with active Wnt signalling, converged on a transcriptional program linked to epithelial-to-mesenchymal transition (EMT) and cell migration, which has important implications for cancer biology.In the third paper, we reveal that p53 functions as transcriptional repressor of FOXQ1 in cancers. Loss of p53 is present in the majority of human cancers and, in synergy with activation of Wnt signalling, could boost FOXQ1 expression, thereby affecting the progression of cancer.Overall, this thesis provides a better understanding of the complexity of Wnt signalling on the molecular level and newly elucidates the function of these two FOX proteins as drivers of oncogenic Wnt pathway activation. Additionally, this new evidence highlights the importance of further in-depth investigation of FOX transcription factors in cancer biology. The relevant role of FOX proteins in the development and progression of cancer is increasingly evident, and in the long run, it will be valuable to characterize the role of FOX factors in a tissue-specific context for the development of targeted cancer therapies.
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| 2. |
- Pizzolato, Giulia, 1990-, et al.
(författare)
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The tumour suppressor p53 is a negative regulator of the carcinoma-associated transcription factor FOXQ1
- 2024
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Ingår i: Journal of Biological Chemistry. - : Elsevier. - 0021-9258 .- 1083-351X. ; 300:4
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Tidskriftsartikel (refereegranskat)abstract
- The forkhead box family transcription factor FOXQ1 is highly induced in several types of carcinomas, where it promotes epithelial-to-mesenchymal transition and tumour metastasis. The molecular mechanisms that lead to FOXQ1 deregulation in cancer are incompletely understood. Here, we used CRISPR/Cas9-based genomic locus proteomics (GLoPro) and promoter reporter constructs to discover transcriptional regulators of FOXQ1, and identified the tumour suppressor p53 as a negative regulator of FOXQ1 expression. ChIP-qPCR as well as complementary gain and loss-of-function assays in model cell lines indicated that p53 binds close to the transcription start site of the FOXQ1 promoter, and that it suppresses FOXQ1 expression in various cell types. Consistently, pharmacological activation of p53 using nutlin-3 or doxorubicin reduced FOXQ1 mRNA and protein levels in cancer cell lines harboring wild-type p53. Finally, we observed that p53 mutations are associated with increased FOXQ1 expression in human cancers. Altogether, these results suggest that loss of p53 function - a hallmark feature of many types of cancer - de-represses FOXQ1, which in turn promotes tumour progression.
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