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- Title
Palmitoylation-driven PHF2 ubiquitination remodels lipid metabolism through the SREBP1c axis in hepatocellular carcinoma.
- Authors
Jeong, Do-Won; Park, Jong-Wan; Kim, Kyeong Seog; Kim, Jiyoung; Huh, June; Seo, Jieun; Kim, Ye Lee; Cho, Joo-Youn; Lee, Kwang-Woong; Fukuda, Junji; Chun, Yang-Sook
- 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. Palmitoylation of proteins can have pathophysiological implications. Here, the authors show that palmitoylation enhances the proteasomal degradation of the histone demethylase PHF2, leading to increased lipogenesis and cell proliferation in an SREBP1c dependent manner and further show that PHF2 acts as an E3 ligase of SREBP1c, suppressing the growth of liver cancer cells.
- Subjects
PROTEOLYSIS; ZINC-finger proteins; UBIQUITINATION; STEROL regulatory element-binding proteins; LIPID metabolism; HEPATOCELLULAR carcinoma; UBIQUITIN ligases; FREE fatty acids
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-42170-0