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정도원Do-Won Jeong

서울대학교 의과대학

CV File 199 kb

Nat. Commun., Oct 12 2023, 14 (1) 6370 | https://doi.org/10.1038/s41467-023-42170-0 Palmitoylation-driven PHF2 ubiquitination remodels lipid metabolism through the SREBP1c axis in hepatocellular carcinoma

Do-Won Jeong ^1,2, Jong-Wan Park^1,3, Kyeong Seog Kim ^1,4, Jiyoung Kim ¹, June Huh ⁵, Jieun Seo ^1,2,6, Ye Lee Kim ^1,2, Joo-Youn Cho ^1,4, Kwang-Woong Lee ⁷, Junji Fukuda ⁶ & Yang-Sook Chun ^1,2,3,*

¹Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.
²Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea.
³Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
⁴Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Korea.
⁵Department of Chemical and Biological Engineering, Korea University, Seoul 02841, Korea.
⁶Faculty of Engineering, Yokohama National University, Yokohama 240-8501, Japan.
⁷Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Korea.

^*Corresponding author: correspondence to Yang-Sook Chun

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.

논문정보

형식Research article
게재일2023년 10월 (BRIC 등록일 2023-10-17)
연구진국내(교신)+국외 연구진
분야 의약학 > 인체시스템의학

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