Regulation of TBXT expression in cancer

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Upregulated levels of TBXT, a transcription factor required during embryogenesis, have been detected in lung, prostate, breast, colon, adenoid cystic and oral squamous cell tumours where its expression is a significant predictor of poor prognosis. In addition, TBXT is a biomarker of a rare cancer of the spinal column called chordoma. While the expression regulation of TBXT is well studied in development, including its autoregulation, which is also detected in chordoma, it is unclear how its expression is initiated in cancers. Using circularised chromosome capture combined with sequencing (4C-seq) we have identified near-cis physical interactions with the TBXT promoter in TBXT expressing and non-expressing cancer cell lines for chordoma, lung, breast and prostate cancer. While many of the TBXT genomic interactions are similar in the cancer types, some of the cell lines show exclusive interactions. A total of nine interactions to the TBXT promoter were found to be distributed in open and active-histone marked genomic regions and three were selected for further testing as putative TBXT regulatory elements using the Self-Transcribing Active Regulatory Region (STARR-seq) luciferase reporter in TBXT expressing or non-expressing lung cancer cells. In addition, a human sequence, related to a mouse TBXT cis-regulatory element (CRE) that drives expression in the mouse embryo and in TBXT-expressing lung cancers cells, was tested for activity in this assay. Of the putative TBXT regulatory elements, two showed significant enhancer activity in either non or TBXT expressing cell lines using the reporter assay, however their activity was not linked to TBXT expression levels, suggesting they do not regulate TBXT expression in these cells. Overall, the study identifies a number of putative regulatory elements which need to be validated further, in in vivo and in vitro models, in addition to luciferase assays, to properly define whether they have a role in regulating expression of TBXT in cancer.
Date of Award1 May 2022
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorFiona Wardle (Supervisor) & Madeline Parsons (Supervisor)

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