Epigenetic factor EPC1 is a master regulator of DNA damage response by interacting with E2F1 to silence death and activate metastasis-related gene signatures

Abstract

Transcription factor E2F1 is a key regulator of cell proliferation and apoptosis. Recently, it has been shown that aberrant E2F1 expression often detectable in advanced cancers contributes essentially to cancer cell propagation and characterizes the aggressive potential of a tumor. Conceptually, this requires a subset of malignant cells capable of evading apoptotic death through anticancer drugs. The molecular mechanism by which the pro-apoptotic activity of E2F1 is antagonized is widely unclear. Here we report a novel function for EPC1 (enhancer of polycomb homolog 1) in DNA damage protection. Depletion of EPC1 potentiates E2F1-mediated apoptosis in response to genotoxic treatment and abolishes tumor cell motility. We found that E2F1 directly binds to the EPC1 promoter and EPC1 vice versa physically interacts with bifunctional E2F1 to modulate its transcriptional activity in a target gene-specific manner. Remarkably, nuclear-colocalized EPC1 activates E2F1 to upregulate the expression of anti-apoptotic survival genes such as BCL-2 or Survivin/BIRC5 and inhibits death-inducing targets. The uncovered cooperativity between EPC1 and E2F1 triggers a metastasis-related gene signature in advanced cancers that predicts poor patient survival. These findings unveil a novel oncogenic function of EPC1 for inducing the switch into tumor progression-relevant gene expression that may help to set novel therapies.

Blockage of the mevalonate pathway overcomes the apoptotic resistance to MEK inhibitors with suppressing the activation of Akt in cancer cells

“…However, the apoptotic resistance to MEK inhibitors is one of the most difficult problems in the expansion of the indication for MEK inhibitors. Considering that we originally discovered these MEK inhibitors by screening for RB-reactivating compounds [ 33 ], it is no wonder that they cannot induce apoptosis well because RB activation restrains the pro-apoptotic activity of E2F1 [ 34 ]. We here demonstrated that the blockade of the mevalonate pathway using statins overcomes the apoptotic resistance to MEK inhibitors with suppression of Akt activation (Figure 7 ).…”

Critical genomic regulation mediated by Enhancer of Polycomb

“…Cisplatin treatment of cancer cell lines, such as SK-Mel-147 melanoma cells, resulted in upregulation of EPC1 , further pointing towards EPC1 enabling survival of cancer cells. Accordingly, knockdown of EPC1 led to increased DNA damage sensitivity and apoptosis in an E2F1-dependent mechanism (Wang et al 2016). …”

Expression level is a key determinant of E2F1-mediated cell fate

“…[11][12][13] To reconcile these contradictory observations, a common explanation is that the action of E2F1 depends on the cellular context, in terms of the presence or absence of differential cofactors, posttranslational modifications or state of other signaling pathways. [14][15][16][17][18][19] Another under-appreciated contribution, however, is the quantitative responses of individual cells to E2F1 levels. Expression levels of endogenous E2F1 can exhibit significant cell-cell variability, which is even higher for exogenous transgenes delivered, for example, via adenoviral transduction.…”