Poster Presentation 25th Lorne Cancer Conference 2013

Characterisation of pro-invasive transcriptional programs regulated by the Fra-1 transcription factor (#158)

Jeannine Diesch 1 , Elaine Sanij 1 , Jason Ellul 1 , Izhak Haviv 2 , Chris Love 3 , Eugene Tulchinsky 4 , John M Mariadason 5 , Oliver Sieber 3 , Ross D Hannan 1 , Amardeep S Dhillon 1
  1. PeterMac Callum Cancer Centre, Melbourne, Vic, Australia
  2. Faculty of Medicine, Bar-Ilan University, Ramat Gan, Israel
  3. Ludwig Institute for Cancer Research, Parkville Branch, Melbourne, Australia
  4. Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom
  5. Ludwig Institute for Cancer Research, Austin Health Heidelberg, Melbourne, Australia

Colorectal cancer (CRC) is the third most common cancer worldwide with invasion and metastatic spread as primary causes of death from this disease. Fos related antigen-1 (Fra-1) is an AP-1 transcription factor frequently over-expressed in a variety of cancers and plays a critical role in driving CRC cell migration and invasion. The aims of this study were to unravel genetic programs orchestrated by Fra-1 in invasive CRC cells.

Stable silencing of Fra-1 in BE CRC cells resulted in dramatic morphological changes, with cells switching from a mesenchymal phenotype to an epithelial-like appearance and complete inhibition of cell migration and invasion. To determine how Fra-1 silencing invokes this striking phenotypic switch, we searched for its transcriptional targets in BE cells using a combination of microarrays to identify Fra-1-regulated genes, and ChIP-Seq to identify genomic binding sites of Fra-1.We found that Fra-1 is bound in close proximity to many genes identified in the microarrays and that the largest ontological class of genes over-represented in both datasets encoded proteins involved in a process describes as epithelial-mesenchymal transition (EMT) (termed Fra-1EMT genes). Amongst these, mesenchymal genes were suppressed upon Fra-1 silencing, whereas epithelial genes were up-regulated. Thus, stable silencing of Fra-1 leads to a reversal of EMT in BE cells. To determine whether changes in the expression of Fra-1EMT genes occur in primary CRCs, we performed unsupervised clustering on existing microarray data from stage B and C CRCs.This analysis demonstrated that the Fra-1EMT signature is associated with poor prognosis in CRC patients. Furthermore, histochemical staining of Fra-1 in CRC specimens revealed that Fra-1 expression is significantly enriched in budding tumour cells, which represent the invasive front of CRCs.

In conclusion, we demonstrate that Fra-1 is a key regulator of transcriptional programs required to maintain EMT in CRC cells.