ApoJ/clusterina: un nuovo soppressore tumorale per il neuroblastoma

Epigenetic reprogramming is an important mechanism of oncogene-induced tumourigenesis. MYCN, a neuronal specific member of the MYC family of transcription factors, is amplified and highly expressed in aggressive, metastatic neuroblastomas. In this study we show that MYCN inhibits the expression of CLUSTERIN (CLU), a potential tumour suppressor gene, by direct interaction with a non canonical E-box sequence in the 5’ flanking region of the CLU promoter. We found that binding of MYCN to the CLU gene causes the appearance of bivalent epigenetic marks, typically observed in the promoters of developmentally regulated genes in stem cells, such as acetylated histones H3/4, di-methylated H3K4 , tri-methylated H3K9-K27, and recruitment of histone deacetylases and polycomb proteins. Tricostatin A and Valproic acid, two inhibitors of histone deacetylases currently used in cancer clinical trials, re-activate the expression of CLU in MYCN amplified neuroblastoma cell lines, causing inhibition of their proliferation and invasive potential. Notably, the effects of the epigenetic drugs are completely abrogated when CLU expression is silenced by RNA interference. This is, to our knowledge, the first study documenting that a MYC oncoprotein can impose a bivalent state and negatively modulate a tumour suppressor gene by direct interaction with an E-box motif. The observation that CLU is an essential mediator of the therapeutic effects of histone deacetylase inhibitors in MYCN-driven tumours suggests that re-activation of CLU in cancer patients could be used to predict a favourable response to epigenetic drugs.