Palmitoylation-driven PHF2 ubiquitination remodels lipid metabolism through the SREBP1c axis in hepatocellular carcinoma

Do Won Jeong, Jong Wan Park, Kyeong Seog Kim, Jiyoung Kim, June Huh, Jieun Seo, Ye Lee Kim, Joo Youn Cho, Kwang Woong Lee, Junji Fukuda, Yang Sook Chun

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Palmitic acid (PA) is the most common fatty acid in humans and mediates palmitoylation through its conversion into palmitoyl coenzyme A. Although palmitoylation affects many proteins, its pathophysiological functions are only partially understood. Here we demonstrate that PA acts as a molecular checkpoint of lipid reprogramming in HepG2 and Hep3B cells. The zinc finger DHHC-type palmitoyltransferase 23 (ZDHHC23) mediates the palmitoylation of plant homeodomain finger protein 2 (PHF2), subsequently enhancing ubiquitin-dependent degradation of PHF2. This study also reveals that PHF2 functions as a tumor suppressor by acting as an E3 ubiquitin ligase of sterol regulatory element-binding protein 1c (SREBP1c), a master transcription factor of lipogenesis. PHF2 directly destabilizes SREBP1c and reduces SREBP1c-dependent lipogenesis. Notably, SREBP1c increases free fatty acids in hepatocellular carcinoma (HCC) cells, and the consequent PA induction triggers the PHF2/SREBP1c axis. Since PA seems central to activating this axis, we suggest that levels of dietary PA should be carefully monitored in patients with HCC.

Original languageEnglish
Article number6370
JournalNature communications
Volume14
Issue number1
DOIs
Publication statusPublished - 2023 Dec

Bibliographical note

Publisher Copyright:
© 2023, Springer Nature Limited.

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy

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