AAV8-ApoE/AAT1-GFP

Metabolic reprogramming is central to oncogene-induced tumorigenesis as it provides essential building blocks and energy sources, but how oncogenic signals control metabolites that play regulatory roles in driving cell proliferation and tumor growth is unclear. Here, researchers show that the oncogenes YAP/TAZ promote polyamine biosynthesis by activating transcription of the rate-limiting enzyme ornithine decarboxylase 1. Increased polyamine levels, in turn, promote oligosaccharylation of eukaryotic translation factor 5A (eIF5A) to support efficient translation of the histone demethylase LSD1. LSD1 is a transcriptional repressor that mediates a large number of YAP/TAZ-downregulated genes, including tumor suppressors in YAP/TAZ-activated cells. Highlighting the importance of the YAP/TAZ-polyamine-eIF5A hypusination-LSD1 axis, inhibition of polyamine biosynthesis or LSD1 suppresses YAP/TAZ-induced cell proliferation and tumor growth. Given the frequent upregulation of YAP/TAZ activity and polyamine levels in different cancers, researchers identify YAP/TAZ as upstream regulators and LSD1 as downstream effector of oncometabolites polyamines, providing a molecular framework in which oncogene-induced metabolic and epigenetic reprogramming coordinately drive tumorigenesis and suggesting potential therapeutic strategies targeting YAP/TAZ- or polyamine-dependent human malignancies.

Here, researchers generated YAP OE;Lsd1^flox/flox mice (or Lsd1^flox/flox as control) and treated the animals with hepatotropic AAV-carrying hepatocyte-specific Cre (AAV8-ApoE/AAT1-Cre) to knock out Lsd1 in the liver (Figure 1a). While AAV8-ApoE/AAT1-Cre treatment had little effect on liver size, histology or cell proliferation in Lsd1^flox/flox animals, the same treatment regime in YAP OE;Lsd1^flox/flox animals remarkably suppressed the changes in liver size, histology and cell proliferation induced by YAP OE (Figure 1b-f). As in mouse livers, LSD1KD by shRNA also significantly inhibited the proliferation of multiple human cancer cell lines with active YAP/TAZ. Consistent with these genetic findings, pharmacologic suppression of LSD1 using the reversible LSD1 inhibitor SP-2577, which is currently in phase I clinical trials for relapsed or refractory Ewing sarcoma and advanced solid tumors, not only suppressed YAP OE-induced liver overgrowth (Figure 1g,h), but also inhibited the proliferation of multiple human cancer cell lines with active YAP/TAZ both in cell culture and in mouse xenograft. These studies indicate that LSD1 is a downstream mediator of the YAP/TAZ-polyamine-eIF5A^Hyp-LSD1 axis.

Figure 1. LSD1 suppression inhibits YAP-induced overgrowth in mouse liver. (Li H, et al., 2022)