Targeting FDFT1 Reduces Cholesterol and Bile Acid Production and Delays Hepatocellular Carcinoma Progression Through
Dong Cai1, Guo-Chao Zhong1, Xin Dai1
1Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
Abstract:
Targeting cholesterol metabolism is a novel direction for tumor therapy. Unfortunately, the current use of statins for hepatocellular carcinoma (HCC) is controversial. Herein, farnesyl-diphosphate farnesyltransferase 1 (FDFT1) is identified as a novel target for treating HCC and a potential alternative to statins. Twenty-three key genes in cholesterol biosynthesis are screened, and FDFT1 is identified via public databases (The Cancer Genome Atlas, International Cancer Genome Consortium and Gene Expression Omnibus). Clinical samples reveal that FDFT1 is highly expressed in HCC tissues, and this phenotype is strongly associated with a poor prognosis. Functionally, FDFT1 knockdown inhibits the proliferation and metastasis of HCC cells and suppresses hepatocarcinogenesis in vitro and in vivo, whereas FDFT1 overexpression promotes HCC cell proliferation and metastasis. Mechanistically, FDFT1 downregulation decreases cholesterol and bile acid levels and then increases hepatocyte nuclear factor 4 alpha (HNF4A) transcriptional activity. Experiments indicate that HNF4A combines with the promoter of aldolase B (ALDOB) and promotes the ALDOB transcription and that ALDOB combines with AKT serine/threonine kinase 1 (AKT1) and inhibits AKT1 phosphorylation. Moreover, FDFT1 knockdown combined with AKT inhibitor (AZD5363) treatment shows remarkable therapeutic potential. FDFT1 inhibition reduces cholesterol and bile acid levels to delay HCC progression through the HNF4A/ALDOB/AKT1 axis. Thus, targeting FDFT1 may be a novel potential strategy for treating HCC.
Insights
Targeting farnesyl-diphosphate farnesyltransferase 1 (FDFT1) shows promise for hepatocellular carcinoma (HCC) therapy. Inhibiting FDFT1 reduces tumor growth and metastasis by modulating cholesterol metabolism via the HNF4A/ALDOB/AKT1 pathway.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Cholesterol metabolism is a potential therapeutic target for hepatocellular carcinoma (HCC).
- Statins, commonly used to target cholesterol, have controversial efficacy in HCC.
- Farnesyl-diphosphate farnesyltransferase 1 (FDFT1) emerges as a novel therapeutic target for HCC.
Purpose of the Study:
- To investigate FDFT1 as a potential therapeutic target for HCC.
- To elucidate the mechanism by which FDFT1 influences HCC progression.
- To evaluate the therapeutic potential of FDFT1 inhibition in HCC.
Main Methods:
- Screening of 23 key cholesterol biosynthesis genes using public databases (TCGA, ICGC, GEO).
- Analysis of FDFT1 expression in HCC clinical samples.
- In vitro and in vivo functional assays (FDFT1 knockdown/overexpression).
- Mechanistic studies involving HNF4A, ALDOB, and AKT1 signaling pathway.
Main Results:
- FDFT1 is highly expressed in HCC tissues and associated with poor prognosis.
- FDFT1 knockdown inhibits HCC cell proliferation and metastasis, while overexpression promotes them.
- FDFT1 downregulation decreases cholesterol and bile acid levels, enhancing HNF4A transcriptional activity.
- FDFT1 inhibition impacts the HNF4A/ALDOB/AKT1 axis, suppressing HCC progression.
- Combined FDFT1 inhibition and AKT inhibitor (AZD5363) show significant therapeutic potential.
Conclusions:
- FDFT1 is a promising novel therapeutic target for HCC.
- Targeting FDFT1 offers a potential alternative to statins for HCC treatment.
- FDFT1 inhibition delays HCC progression by modulating cholesterol metabolism through the HNF4A/ALDOB/AKT1 pathway.
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