Department of Physiology, School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China; Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
Redox Biol. 2023 Jun;62:102705. doi: 10.1016/j.redox.2023.102705. Epub 2023 Apr 17.
The eukaryotic ribosome is essential for cancer cell survival. Perturbation of ribosome biogenesis induces nucleolar stress or ribosomal stress, which restrains cancer growth, as rapidly proliferating cancer cells need more active ribosome biogenesis. In this study, we found that UTP11 plays an important role in the biosynthesis of 18S ribosomal RNAs (rRNA) by binding to the pre-rRNA processing factor, MPP10. UTP11 is overexpressed in human cancers and associated with poor prognoses. Interestingly, depletion of UTP11 inhibits cancer cell growth in vitro and in vivo through p53-depedednt and -independent mechanisms, whereas UTP11 overexpression promotes cancer cell growth and progression. On the one hand, the ablation of UTP11 impedes 18S rRNA biosynthesis to trigger nucleolar stress, thereby preventing MDM2-mediated p53 ubiquitination and degradation through ribosomal proteins, RPL5 and RPL11. On the other hand, UTP11 deficiency represses the expression of SLC7A11 by promoting the decay of NRF2 mRNA, resulting in reduced levels of glutathione (GSH) and enhanced ferroptosis. Altogether, our study uncovers a critical role for UTP11 in maintaining cancer cell survival and growth, as depleting UTP11 leads to p53-dependent cancer cell growth arrest and p53-independent ferroptosis.
真核核糖体对癌细胞的存活至关重要。核糖体生物发生的扰动会诱导核仁应激或核糖体应激，从而抑制癌症的生长，因为快速增殖的癌细胞需要更活跃的核糖体生物发生。在这项研究中，我们发现 UTP11 通过与 pre-rRNA 加工因子 MPP10 结合，在 18S 核糖体 RNA(rRNA)的生物合成中发挥重要作用。UTP11 在人类癌症中过度表达，并与不良预后相关。有趣的是，通过 p53 依赖性和非依赖性机制，耗尽 UTP11 可抑制体外和体内的癌细胞生长，而 UTP11 的过表达则促进癌细胞的生长和进展。一方面，UTP11 的缺失会阻碍 18S rRNA 的生物合成，从而引发核仁应激，从而阻止 RPL5 和 RPL11 等核糖体蛋白介导的 MDM2 介导的 p53 泛素化和降解。另一方面，UTP11 缺乏通过促进 NRF2 mRNA 的降解来抑制 SLC7A11 的表达，导致谷胱甘肽 (GSH) 水平降低和铁死亡增强。总之，我们的研究揭示了 UTP11 在维持癌细胞存活和生长中的关键作用，因为耗尽 UTP11 会导致 p53 依赖性癌细胞生长停滞和 p53 非依赖性铁死亡。
