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Published on: July 12, 2018
L-methionine promotes CD8+ T cells killing hepatocellular carcinoma by inhibiting NR1I2/PCSK9 signaling
Chengsha Yuan1, Changpeng Hu1, Huyue Zhou1
1Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, China.
Background:
Liver cancer has consistently high incidence and mortality rates among malignant tumors. PCSK9, a target for hypercholesterolemia therapy, has recently been identified as an inhibitor of anti-tumor immunity, and targeting PCSK9 effectively inhibits tumor progression. However, small molecule inhibitors are lacking due to its flat protein structure.
Methods:
PCSK9 transcription inhibitor screening was conducted using a PCSK9 promoter-driven td-Tomato plasmid. Quantitative real-time PCR and immunoblotting were employed to assess the effect of L-methionine on PCSK9 expression in HCC cell lines. Co-culture experiments were performed to evaluate the impact of L-methionine on CD8+ T cell-mediated killing of liver cancer cells. RNA sequencing, CUT&Tag, gene editing, and luciferase reporter assays were utilized to identify the transcription factor regulating PCSK9. Additionally, liver cancer xenograft and spontaneous liver cancer mouse models were used to evaluate the anti-cancer efficacy of L-methionine.
Results:
Our study identified L-methionine, an essential amino acid, as a transcriptional inhibitor of PCSK9. The optimal dose of L-methionine to inhibit PCSK9 expression and enhance CD8+ T cell-mediated killing of liver cancer cells in vitro is 50 μM. Furthermore, intraperitoneal injection of 5 mg/kg/day of L-methionine significantly inhibited tumor growth in both liver cancer xenograft and spontaneous liver cancer mouse models. Mechanistically, we identified NR1I2 as a key transcription factor for PCSK9 and their crucial binding site was TGCACCCTGACAC. L-methionine inhibits PCSK9 transcription by downregulating NR1I2.
Conclusions:
This work demonstrates that L-methionine promotes CD8+ T cell-mediated killing of hepatocellular carcinoma by inhibiting NR1I2/PCSK9 signaling. Our study introduces a novel and convenient approach to inhibit PCSK9 and provides a theoretical basis for the rational supplementation of L-methionine in liver cancer patients.
Insights
L-methionine inhibits liver cancer progression by downregulating NR1I2/PCSK9 signaling, enhancing CD8+ T cell immunity. This essential amino acid offers a novel therapeutic strategy for hepatocellular carcinoma.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Liver cancer presents high incidence and mortality rates.
- PCSK9, a target for hypercholesterolemia, inhibits anti-tumor immunity, but lacks small molecule inhibitors.
- Targeting PCSK9 is a promising strategy for inhibiting liver cancer progression.
Purpose of the Study:
- To identify novel inhibitors of PCSK9.
- To investigate the role of L-methionine in regulating PCSK9 expression and anti-tumor immunity in liver cancer.
- To elucidate the molecular mechanisms underlying L-methionine's anti-cancer effects.
Main Methods:
- Screening for PCSK9 transcription inhibitors using a reporter plasmid.
- Assessing L-methionine's effect on PCSK9 expression in HCC cell lines via qPCR and immunoblotting.
- Evaluating L-methionine's impact on CD8+ T cell-mediated killing and tumor growth in mouse models.
Main Results:
- L-methionine was identified as a transcriptional inhibitor of PCSK9.
- Optimal L-methionine dose (50 μM) enhanced CD8+ T cell killing of liver cancer cells in vitro.
- L-methionine (5 mg/kg/day) significantly inhibited tumor growth in vivo by downregulating NR1I2, a key transcription factor for PCSK9.
Conclusions:
- L-methionine promotes CD8+ T cell-mediated killing of hepatocellular carcinoma by inhibiting NR1I2/PCSK9 signaling.
- L-methionine presents a novel and convenient approach to inhibit PCSK9.
- This study provides a basis for L-methionine supplementation in liver cancer therapy.
