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Elevated choline drives KLF5-dominated transcriptional reprogramming to facilitate liver cancer progression
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Elevated choline drives KLF5-dominated transcriptional reprogramming to facilitate liver cancer progression
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Journal Article
Elevated choline drives KLF5-dominated transcriptional reprogramming to facilitate liver cancer progression
2024
Overview
An increase in the total choline-containing compound content is a common characteristic of cancer cells, and aberrant choline metabolism in cancer is closely associated with malignant progression. However, the potential role of choline-induced global transcriptional changes in cancer cells remains unclear. In this study, we reveal that an elevated choline content facilitates hepatocellular carcinoma (HCC) cell proliferation by reprogramming Krüppel-like factor 5 (KLF5)-dominated core transcriptional regulatory circuitry (CRC). Mechanistically, choline administration leads to elevated S-adenosylmethionine (SAM) levels, inducing the formation of H3K4me1 within the super-enhancer (SE) region of KLF5 and activating its transcription. KLF5, as a key transcription factor (TF) of CRC established by choline, further transactivates downstream genes to facilitate HCC cell cycle progression. Additionally, KLF5 can increase the expression of choline kinase-α (CHKA) and CTP:phosphocholine cytidylyltransferase (CCT) resulting in a positive feedback loop to promote HCC cell proliferation. Notably, the histone deacetylase inhibitor (HDACi) vorinostat (SAHA) significantly suppressed KLF5 expression and liver tumor growth in mice, leading to a prolonged lifespan. In conclusion, these findings highlight the epigenetic regulatory mechanism of the SE-driven key regulatory factor KLF5 conducted by choline metabolism in HCC and suggest a potential therapeutic strategy for HCC patients with high choline content.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/51
/ 38/77
/ 38/91
/ 64/60
/ 82/29
/ Animals
/ Carcinoma, Hepatocellular - drug therapy
/ Carcinoma, Hepatocellular - genetics
/ Carcinoma, Hepatocellular - metabolism
/ Carcinoma, Hepatocellular - pathology
/ Cellular Reprogramming - genetics
/ Choline
/ CTP:phosphocholine cytidylyltransferase
/ Gene Expression Regulation, Neoplastic - drug effects
/ Humans
/ Kruppel-Like Transcription Factors - genetics
/ Kruppel-Like Transcription Factors - metabolism
/ Liver Neoplasms - drug therapy
/ Liver Neoplasms - metabolism
/ Medicine
/ Mice
/ Oncology
