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 and Yang-Sook Chun ()
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Do-Won Jeong: Seoul National University College of Medicine
Jong-Wan Park: Seoul National University College of Medicine
Kyeong Seog Kim: Seoul National University College of Medicine
Jiyoung Kim: Seoul National University College of Medicine
June Huh: Korea University
Jieun Seo: Seoul National University College of Medicine
Ye Lee Kim: Seoul National University College of Medicine
Joo-Youn Cho: Seoul National University College of Medicine
Kwang-Woong Lee: Seoul National University College of Medicine
Junji Fukuda: Yokohama National University
Yang-Sook Chun: Seoul National University College of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42170-0

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