The E2F4/p130 repressor complex cooperates with oncogenic DNp73a to promote cell survival

Tumor suppressor p53 and its related proteins, p63 and p73, can be synthesized as multiple isoforms lacking part of the N- or C-terminal regions. Specifically, high expression of the DNp73a isoform is notoriously associated with poor prognosis in cancer. Here, we have performed proteomics analysis of DNp73a, using as a cellular model human papillomavirus type 38-transformed keratinocytes (38HK) that express high levels of this isoform. We find that DNp73a associates with the E2F4/p130 repressor complex through a direct interaction with E2F4. Remarkably, this interaction is favored by the N-terminal truncation of p73 characteristic of DNp73 isoforms and is independent of the C-terminal splicing status. We show that the DNp73a-E2F4/p130 complex is recruited to the promoters of specific genes, thereby enforcing inhibition of their expression both in 38HK and in cancer-derived cell lines. Consistently, silencing of E2F4 in 38HK and in cancer cells resulted in induction of senescence. In conclusion, we have identified and characterized a novel transcriptional regulatory complex that exerts pro-proliferative functions in transformed cells.