PMC

(A) In vivo process by which cancer cells acquire oncogene addiction. (B) The table compares different types of cells with respect to tumorigenic properties and oncogene addiction.

Strategies to control oncogene expression in zebrafish cancer models. (a) Spatial regulation of oncogene (ONC) expression through the activity of tissue-specific promoter (tsp). (b) The Gal4/ UAS system to enable cell type specific oncogene expression. The yeast transcription factor Gal4 is expressed through the control of a tissue-specific promoter (tsp) and binds to the upstream activating sequence (UAS) to drive the expression of the oncogene (ONC). (c) Cre-mediated oncogene (ONC) expression. Cre-mediated recombination removes an intervening sequence and places the oncogene under the control of a promoter. (d) Temporal oncogene (ONC) activation through the induction of the activity of the heat shock promoter. (e) Temporal oncogene (ONC) activation using the Tet-ON system. The binding of doxycycline to rtTA allows the transcription factor to bind and activate transcription at tetO responsive elements (TRE)-containing promoters. (f) Ligand-dependent oncogene (ONC) activation. Fusing the ligand-binding domain (LBD) onto oncogenic transcription factors (MYC), transcription factors (LexA) or Cre recombinase confers ligand-dependent activities to these proteins. Strategies to spatially control oncogene expression are boxed in green, whereas temporal to control of oncogene expression is boxed in red.

(A) A table summarizing the results of this study. (B) Schematic diagram showing how oncogene addiction is acquired.

Control of CTCF-mediated chromatin topology in cancer. (A) CTCF-mediated chromatin insulation: in a normal cell, DNA hypermethylation disrupts CTCF binding and looping, leading to abrogation of chromatin insulation, gain of enhancer–promoter interaction and transcription activation of tumour suppressor gene (TSG) or transcription repression of an oncogene. In a cancer cell, DNA hypomethylation facilitates CTCF binding and looping, leading to establishment of chromatin insulation, loss of enhancer–promoter interaction and transcription inactivation of tumour suppressor gene (TSG) or transcription activation of an oncogene. Epigenetic editing of CTCF-binding sites on the insulation anchors for TSG (dCas9-DNMT3a) and oncogene (dCas9-TET1) can lead to blockage or creation of CTCF insulation, gain or loss of enhancer–promoter interaction and transcription activation or inactivation for TSG and oncogene, respectively, in cancer cell. (B) CTCF-mediated long-range enhancer–promoter interaction: in a normal cell, CTCF binding on TSG promoter leads to establishment of enhancer–promoter interaction and transcription activation of TSG (vice versa for oncogene). In a cancer cell, loss of CTCF binding on TSG promoter leads to abrogation of enhancer–promoter interaction and transcription inactivation of TSG (vice versa for oncogene). Artificial tethering of CTCF on the TSG promoter via dCas9-gRNA approach can re-establish the enhancer–promoter interaction and transcription activation of TSG in cancer cell. Deletion of CTCF motif via Cas9-gRNA approach disrupts CTCF binding on the oncogene promoter, leading to abrogation of enhancer–promoter interaction and transcription inactivation of oncogene in cancer cells.