Palmitoylation-driven PHF2 ubiquitination remodels lipid metabolism through the SREBP1c axis in hepatocellular carcinoma
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Updated: Jul 13, 2025

Analysis of SCAP N-glycosylation and Trafficking in Human Cells
Published on: November 8, 2016
Do-Won Jeong1,2, Jong-Wan Park1,3, Kyeong Seog Kim1,4
1Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea.
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.
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