Editors' ChoiceCancer

Predictive biomarkers for HDAC inhibitor efficacy

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Sci. Signal.  05 Jul 2016:
Vol. 9, Issue 435, pp. ec155
DOI: 10.1126/scisignal.aah4647

Epigenetic changes are frequent in cancer. Inhibitors of histone deacetylases show efficacy against cancer cells but lack predictive biomarkers and can be prohibitively toxic in patients. ΔNp63 is an oncogenic isoform of p63, a member of the p53 family of transcription factors, and is critical to the proliferation of p53-null lymphomas. Napoli et al. found a predictive biomarker for HDAC inhibitor efficacy in ΔNp63-positive tumors. A drug screen in MCF10A mammary epithelial cells identified several HDAC inhibitors that reduced the abundance of ΔNp63 and the expression of one of its target genes, DGCR8, which encodes a microRNA (miRNA) processing component. The abundance of ΔNp63 transcripts was unaffected in various cell lines treated with HDAC inhibitors, and both ΔNp63 abundance and DGCR8 expression were rescued by treatment with a proteasome inhibitor, indicating that HDAC inhibitors decreased the stability of ΔNp63 protein. Among the E3 ubiquitin ligases known to mark ΔNp63 for degradation, only knockdown of FBW7 prevented the effects of HDAC inhibition in two ΔNp63-positive cancer cell lines. In a larger panel of human cancer cell lines and patient biopsies, FBW7 abundance positively correlated with sensitivity to HDAC inhibitors. Sequencing and functional analyses revealed that in cells with high, but not low, amounts of FBW7, the abundance of two miRNAs, let-7d and miR-128, was dependent on ΔNp63-mediated expression of DGCR8 and thus was suppressed by HDAC inhibitors. Treating cells with miRNA inhibitors targeting let-7d and miR-128 mimicked the cytotoxicity of HDAC inhibitors, whereas overexpressing DGCR8 or let-7d and miR-128 prevented it. Genetically engineered or xenograft mouse models confirmed the cell culture findings. The expression of CDKN1A, the transcript encoding cyclin-dependent kinase inhibitor p21, is suppressed by both let-7d and miR-128 and is not only induced by HDAC inhibitors but is important for their effects. Knocking down p21 partially prevented the cytotoxic effects of miRNA or HDAC inhibition in cancer cells. The findings describe a mechanism by which HDAC inhibitors induce cell death and indicate that high abundance of FBW7 may be predictive of their efficacy in some tumors.

M. Napoli, A. Venkatanarayan, P. Raulji, B. A. Meyers, W. Norton, L. S. Mangala, A. K. Sood, C. Rodriguez-Aguayo, G. Lopez-Berestein, H. Vin, M. Duvic, M. B. Tetzlaff, J. L. Curry, A. H. Rook, H. A. Abbas, C. Coarfa, P. H. Gunaratne, K. Y. Tsai, E. R. Flores, ΔNp63/DGCR8-dependent microRNAs mediate therapeutic efficacy of HDAC inhibitors in cancer. Cancer Cell 29, 874–888 (2016). [PubMed]