Background

The tumour suppressor gene RASSF1A is inactivated through point mutation or promoter hypermethylation in the majority of human cancers. RASSF1A silencing is the most widely reported epigenetic event in sporadic human malignancies and has increasingly prognostic value, e.g. in lung, breast and bladder. We have been focusing on the consequence of RASSF1A loss to tumour initiation and radiation sensitivity.

Method

We performed a genetic screen in mice using Sleeping Beauty (SB) transposon-mediated insertional mutagenesis, to identify candidate genes associated with tumourigenesis in the absence of Rassf1a. From the resulting leukemias/lymphomas that developed in these mice, we identified 10 genes potentially associated with tumour formation in the absence of Rassf1a. We further analysed the synergy of the 2 hit model of tumour suppression by monitoring biochemical pathway activation and cellular proliferation assays.

Results

One of the top hits in our screen was the terminal differentiation transcription factor Runx2. Here, we describe how loss of RASSF1A promotes oncogenic YAP1-TEAD complexes and how RUNX2, p73 and TEAD effectively compete for YAP1 association. Together loss of both RASSF1A and RUNX2 exacerbate YAP1-TEAD levels consistent with the multi-step nature of cancer. We show that RUNX2 expression is frequently down-regulated in various cancers associated with poorer survival in patients with diffuse large B-cell lymphomas. Interestingly, concordant decreased expression levels of RASSF1 and RUNX2 were observed in both precursor T-cell acute lymphoblastic leukemia and colorectal cancer.

Conclusion

Dual regulation of YAP-TEAD promotes oncogenic activity, thus providing a novel mechanism for RASSF1A-mediated tumour suppression.