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Unspliced XBP1 contributes to cholesterol biosynthesis and tumorigenesis by stabilizing SREBP2 in hepatocellular carcinoma
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Unspliced XBP1 contributes to cholesterol biosynthesis and tumorigenesis by stabilizing SREBP2 in hepatocellular carcinoma
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Journal Article
Unspliced XBP1 contributes to cholesterol biosynthesis and tumorigenesis by stabilizing SREBP2 in hepatocellular carcinoma
2022
Overview
Cholesterol biosynthesis plays a critical role in rapidly proliferating tumor cells. X-box binding protein 1 (XBP1), which was first characterized as a basic leucine zipper-type transcription factor, exists in an unspliced (XBP1-u) and spliced (XBP1-s) form. Recent studies showed that unspliced XBP1 (XBP1-u) has unique biological functions independent from XBP1-s and could promote tumorigenesis; however, whether it is involved in tumor metabolic reprogramming remains unknown. Herein, we found that XBP1-u promotes tumor growth by enhancing cholesterol biosynthesis in hepatocellular carcinoma (HCC) cells. Specifically, XBP1-u colocalizes with sterol regulatory element-binding protein 2 (SREBP2) and inhibits its ubiquitination/proteasomal degradation. The ensuing stabilization of SREBP2 activates the transcription of 3-hydroxy-3-methylglutaryl-CoA reductase (
HMGCR
), a rate-limiting enzyme in cholesterol biosynthesis. We subsequently show that the XBP1-u/SREBP2/HMGCR axis is crucial for enhancing cholesterol biosynthesis and lipid accumulation as well as tumorigenesis in HCC cells. Taken together, these findings reveal a novel function of XBP1-u in promoting tumorigenesis through increased cholesterol biosynthesis in hepatocarcinoma cells. Hence, XBP1-u might be a potential target for anti-tumor therapeutic strategies that focus on cholesterol metabolism in HCC.
Publisher
Springer Science and Business Media LLC,Springer International Publishing,Springer Nature B.V
Subject
Activating transcription factor 1
/ Biomedical and Life Sciences
/ Carcinoma, Hepatocellular - genetics
/ Cell Transformation, Neoplastic
/ hepatoma
/ Humans
/ Hydroxymethylglutaryl-CoA reductase
/ Leucine
/ Lipids
/ Liver Neoplasms - metabolism
/ Original
/ Proteins
/ Sterol Regulatory Element Binding Protein 2
/ Sterol Regulatory Element Binding Protein 2 - genetics
/ Sterol Regulatory Element Binding Protein 2 - metabolism
/ Sterol regulatory element-binding protein
/ Tumors
