NUDT21 suppresses the growth of small cell lung cancer by modulating GLS1 splicing

Biochem Biophys Res Commun. 2020 May 28;526(2):431-438. doi: 10.1016/j.bbrc.2020.03.089. Epub 2020 Mar 27.

Abstract

The mRNA precursor 3'-end modification factor NUDT21 is a major regulator of 3'UTR shortening and an important component of pre-mRNA cleavage and polyadenylation. However, its role in pathologic progress of small cell lung cancer (SCLC) remains unclear. In this study, we observed that NUDT21 expression is downregulated in SCLC tissues. Hypoxia-induced down-regulation of NUDT21 through HIF-1α. NUDT21 shRNA transduction promotes proliferation and inhibits apoptosis of A549 cells. NUDT21 inhibition also promotes tumor growth in a mouse xenograft model. Furthermore, we clarified that HIF-1α mediated NUDT21 downregulation which altered the expression patterns of two isoforms of GLS1, GAC and KGA. These results link the hypoxic tumor environments to aberrant glutamine metabolism which is important for cellular energy in SCLC cells. Therefore, NUDT21 could be considered as a potential target for the treatment of SCLC.

Keywords: GLS1; HIF-1α; Hypoxic; NUDT21; SCLC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Cell Proliferation / genetics
  • Cells, Cultured
  • Cleavage And Polyadenylation Specificity Factor / metabolism*
  • Glutaminase / genetics*
  • Glutaminase / metabolism
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • MicroRNAs / genetics
  • Polyadenylation
  • RNA Splicing / genetics*
  • Small Cell Lung Carcinoma / genetics*
  • Small Cell Lung Carcinoma / metabolism
  • Small Cell Lung Carcinoma / pathology*

Substances

  • Cleavage And Polyadenylation Specificity Factor
  • MicroRNAs
  • Nudt21 protein, human
  • GLS protein, human
  • Glutaminase