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NSUN2 Knockdown Promotes the Ferroptosis of Colorectal Cancer Cells Via m5C Modification of SLC7A11 mRNA
Ruibing Tong1, Yuefeng Li2, Junli Wang2
1Gastrointestinal Surgery, The First Affiliated Hospital of the Baotou Medical College of Inner Mongolia University of Science and Technology, No. 41 Liyin Road, Kundulun District, Baotou, China. trbing810704@163.com.
Abstract:
The high occurrence and death rates of colorectal cancer (CRC) make it a major health concern. Recent studies have identified NOP2/Sun RNA methyltransferase family member 2 (NSUN2), an RNA methyltransferase, as a key regulator in various tumor types. However, how exactly NSUN2-mediated m5C alteration affects CRC is still a mystery. This study seeks to understand how NSUN2 contributes to the growth and death of colorectal cancer cells. New tissue samples were taken in order to investigate NSUN2 expression in CRC. In vitro tests were performed to evaluate NSUN2's function. We used m5C-methylated-RNA immunoprecipitation and RNA stability experiments to find out how NSUN2 works on Solute carrier family 7 member 11 (SLC7A11, also called xCT). Downregulation of NSUN2 limits CRC cell growth and induces ferroptosis, as we show that NSUN2 was substantially expressed in CRC. In terms of the molecular mechanism, NSUN2 controls the translation and stability of SLC7A11 mRNA by regulating its m5C methylation. Functional tests show that SLC7A11 compensates for the NSUN2 knockdown-induced decrease in cell proliferation. Additionally, SLC7A11 overexpression restores ferroptosis to CRC cells after NSUN2 knockdown. These findings emphasize NSUN2's crucial role in modulating colorectal cancer cell growth and survival via SLC7A11, pointing to promising new therapeutic targets.
Insights
NOP2/Sun RNA methyltransferase family member 2 (NSUN2) promotes colorectal cancer (CRC) growth and survival. Inhibiting NSUN2 limits CRC cell proliferation and induces ferroptosis by regulating SLC7A11 mRNA stability.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Colorectal cancer (CRC) presents high mortality rates globally.
- NSUN2, an RNA methyltransferase, is implicated in various cancers.
- The precise role of NSUN2 in CRC pathogenesis remains unclear.
Purpose of the Study:
- To investigate the role of NSUN2 in colorectal cancer cell growth and death.
- To elucidate the molecular mechanism by which NSUN2 influences CRC.
- To identify NSUN2 as a potential therapeutic target for CRC.
Main Methods:
- Analysis of NSUN2 expression in colorectal cancer tissue samples.
- In vitro functional assays to assess NSUN2's role in CRC cells.
- m5C-methylated-RNA immunoprecipitation and RNA stability assays to determine NSUN2's mechanism of action on SLC7A11.
- Assessment of SLC7A11's role in compensating for NSUN2 knockdown effects.
Main Results:
- NSUN2 is significantly expressed in colorectal cancer tissues.
- Downregulation of NSUN2 inhibits CRC cell growth and induces ferroptosis.
- NSUN2 regulates the translation and stability of SLC7A11 mRNA via m5C methylation.
- SLC7A11 can rescue CRC cells from NSUN2 knockdown-induced proliferation defects and ferroptosis.
Conclusions:
- NSUN2 plays a critical role in colorectal cancer cell proliferation and survival.
- NSUN2 modulates CRC progression through the regulation of SLC7A11.
- Targeting NSUN2 and its downstream effector SLC7A11 offers a promising therapeutic strategy for colorectal cancer.
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