Elevated choline drives KLF5-dominated transcriptional reprogramming to facilitate liver cancer progression.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE

Publication: <2002->: Basingstoke : Nature Publishing Group
Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-

Liver Neoplasms*/genetics ; Liver Neoplasms*/pathology ; Liver Neoplasms*/metabolism ; Liver Neoplasms*/drug therapy ; Choline*/metabolism ; Kruppel-Like Transcription Factors*/genetics ; Kruppel-Like Transcription Factors*/metabolism ; Carcinoma, Hepatocellular*/genetics ; Carcinoma, Hepatocellular*/pathology ; Carcinoma, Hepatocellular*/metabolism ; Carcinoma, Hepatocellular*/drug therapy ; Cell Proliferation* ; Gene Expression Regulation, Neoplastic*/drug effects ; Disease Progression*; Humans ; Animals ; Mice ; Cell Line, Tumor ; Choline Kinase/genetics ; Choline Kinase/metabolism ; Vorinostat/pharmacology ; Cellular Reprogramming/genetics ; Mice, Nude

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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

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82121004 National Natural Science Foundation of China (National Science Foundation of China); 81930123 National Natural Science Foundation of China (National Science Foundation of China)

N91BDP6H0X (Choline)
0 (Kruppel-Like Transcription Factors)
0 (KLF5 protein, human)
EC 2.7.1.32 (Choline Kinase)
EC 2.7.1.32 (CHKA protein, human)
58IFB293JI (Vorinostat)

Date Created: 20240909 Date Completed: 20241014 Latest Revision: 20241016

20241016

10.1038/s41388-024-03150-w

39251845