Open AccessYAP/TAZ drives cell proliferation and tumour growth via a polyamine–eIF5A hypusination–LSD1 axis
Author(s) -
Hongde Li,
Bo-Tsung Wu,
Mohammed Kanchwala,
Jing Cai,
Li Wang,
Chao Xing,
Yonggang Zheng,
Duojia Pan
Publication year - 2022
Publication title -
nature cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 11.38
H-Index - 369
eISSN - 1476-4679
pISSN - 1465-7392
DOI - 10.1038/s41556-022-00848-5
Subject(s) - polyamine , ornithine decarboxylase , microbiology and biotechnology , cell growth , biology , carcinogenesis , hippo signaling pathway , downregulation and upregulation , transcription factor , effector , cancer research , chemistry , biochemistry , gene , enzyme
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.