HSF1 Links Ribosome Activity and Metabolic Reprogramming

To sustain high rates of anabolic metabolism and cellular proliferation, malignant cells increase ribosome biogenesis and translational activity. However, it is unclear whether changes in translational activity contribute to the modulation of transcriptional responses. Santagata and colleagues found that inhibitors of translation elongation such as cycloheximide induced substantial changes in mRNA expression in particular genes regulated by heat shock transcription factor 1 (HSF1).Translation inhibition abrogated HSF1 binding to the promoters of genes that enhance tumor growth and progression without affecting HSF1 expression. In addition, an HSF1 inactivation gene expression signature was enriched in cancer cell lines treated with translation inhibitors or subjected to downregulation of ribosome subunits, supporting the idea that translational flux regulates HSF1 activity. Analysis of a high-throughput chemical screen identified the natural product rocaglamide A, which blocks translation initiation via inhibition of eukaryotic translation initiation factor 4A, and its analogue, rohinitib, as potent inhibitors of HSF1 transcriptional activity. Rohinitib selectively diminished HSF1 promoter binding and target gene expression in various human cancer cell lines and stimulated expression of thioredoxin-interacting protein (TXNIP), a negative regulator of glucose uptake, resulting in metabolic reprogramming of cancer cells. Intriguingly, both early-stage neoplastic cells characterized by HSF1 activation and a diverse panel of aggressive cancer cell lines exhibited increased sensitivity to inhibition of translation initiation with rohinitib compared with nontransformed cells. Of note, rohinitib treatment suppressed the growth of xenograft tumors derived from human acute myeloid leukemia cells; this antitumor activity was associated with decreased expression of HSF1 target genes, upregulated TXNIP mRNA expression, and inhibition of glucose uptake in vivo. These findings identify a link between the ribosome and HSF1 in the regulation of transcription and metabolism and suggest that cancer cells may be selectively vulnerable to blockade of translation initiation.

Santagata S, Mendillo ML, Tang YC, Subramanian A, Perley CC, Roche SP, et al. Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science 2013;341:1238303.