YAP/TAZ drives cell proliferation and tumour growth via a polyamine–eIF5A hypusination–LSD1 axis

• Published in: Nature cell biology Vol. 24; no. 3; pp. 373 - 383
• Main Authors: Li, Hongde, Wu, Bo-Kuan, Kanchwala, Mohammed, Cai, Jing, Wang, Li, Xing, Chao, Zheng, Yonggang, Pan, Duojia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2022; Nature Publishing Group
• Subjects: 13/106; 13/109; 13/51; 14/63; 38/1; 38/77; 38/91; 42; 631/67/68/2486; 631/80/86; 692/699/67; 692/699/67/2327; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Biomedical and Life Sciences; Biosynthesis; Cancer Research; Carcinogenesis - genetics; Cell Biology; Cell growth; Cell proliferation; Cell Proliferation - genetics; Developmental Biology; Energy sources; Epigenetics; Gene expression; Genes; Histone Demethylases - genetics; Histone Demethylases - metabolism; Histones; Humans; Life Sciences; Metabolism; Metabolites; Neoplasms - genetics; Neoplasms - pathology; Ornithine decarboxylase; Phosphoproteins - genetics; Phosphoproteins - metabolism; Polyamines; Stem Cells; Suppressors; Trans-Activators - metabolism; Transcription; Translation; Tumorigenesis; Tumors; YAP-Signaling Proteins; Yes-associated protein
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-022-00848-5

Metabolic reprogramming is central to oncogene-induced tumorigenesis by providing the necessary building blocks and energy sources, but how oncogenic signalling controls metabolites that play regulatory roles in driving cell proliferation and tumour growth is less understood. Here we show that oncogene YAP/TAZ promotes polyamine biosynthesis by activating the transcription of the rate-limiting enzyme ornithine decarboxylase 1. The increased polyamine levels, in turn, promote the hypusination of eukaryotic translation factor 5A (eIF5A) to support efficient translation of histone demethylase LSD1, a transcriptional repressor that mediates a bulk of YAP/TAZ-downregulated genes including tumour suppressors in YAP/TAZ-activated cells. Accentuating the importance of the YAP/TAZ–polyamine–eIF5A hypusination–LSD1 axis, inhibiting polyamine biosynthesis or LSD1 suppressed YAP/TAZ-induced cell proliferation and tumour growth. Given the frequent upregulation of YAP/TAZ activity and polyamine levels in diverse cancers, our identification of YAP/TAZ as an upstream regulator and LSD1 as a downstream effector of the oncometabolite polyamine offers a molecular framework in which oncogene-induced metabolic and epigenetic reprogramming coordinately drives tumorigenesis, and suggests potential therapeutic strategies in YAP/TAZ- or polyamine-dependent human malignancies. Li et al. show that YAP/TAZ directly promotes polyamine biosynthesis and activates eIF5A activity to upregulate LSD1 expression, thereby suppressing various genes including tumour suppressors to enhance tumour growth.