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NUDT21 suppresses the growth of small cell lung cancer by modulating GLS1 splicing
Chuan-Cheng Gao1, Qin-Qin Xu2, Feng-Jun Xiao3
1Graduate School of Anhui Medical University, Hefei, PR China; Beijing Institute of Radiation Medicine, Beijing, PR China.
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.
Insights
NUDT21, a key regulator of mRNA processing, is downregulated in small cell lung cancer (SCLC) due to hypoxia. Its inhibition promotes SCLC cell proliferation and tumor growth, suggesting NUDT21 as a potential therapeutic target.
Area of Science:
- Molecular Biology
- Oncology
- Cancer Research
Background:
- NUDT21 regulates mRNA 3'UTR shortening and pre-mRNA cleavage/polyadenylation.
- The role of NUDT21 in the pathology of small cell lung cancer (SCLC) is not well understood.
Purpose of the Study:
- To investigate the role of NUDT21 in SCLC progression.
- To elucidate the mechanism of NUDT21 regulation in SCLC.
Main Methods:
- Analysis of NUDT21 expression in SCLC tissues.
- Investigating the effect of NUDT21 knockdown on A549 cell proliferation and apoptosis.
- Utilizing a mouse xenograft model to assess tumor growth.
- Examining the regulatory pathway involving HIF-1α and GLS1 isoforms.
Main Results:
- NUDT21 expression is significantly downregulated in SCLC tissues.
- Hypoxia, mediated by HIF-1α, induces NUDT21 downregulation.
- NUDT21 inhibition using shRNA enhances A549 cell proliferation and reduces apoptosis.
- NUDT21 suppression promotes tumor growth in vivo.
- HIF-1α-mediated NUDT21 downregulation alters GLS1 isoform expression (GAC and KGA), impacting glutamine metabolism in SCLC cells.
Conclusions:
- NUDT21 downregulation, driven by hypoxia via HIF-1α, contributes to SCLC progression.
- The altered expression of GLS1 isoforms due to NUDT21 inhibition links hypoxia to aberrant glutamine metabolism in SCLC.
- NUDT21 represents a potential therapeutic target for SCLC treatment.
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