Acetylation-induced PCK isoenzyme transition promotes metabolic adaption of liver cancer to systemic therapy

Zongpan Jing, Jiajia Gao, Jun Li, Fangfei Niu, Lusong Tian, Peng Nan, Yan Sun, Xiufeng Xie, Ying Zhu, Yan Zhao, Fang Liu, Lanping Zhou, Yulin Sun, Xiaohang Zhao

Research output: Contribution to journalArticlepeer-review

Abstract

Sorafenib and lenvatinib are approved first-line targeted therapies for advanced liver cancer, but most patients develop acquired resistance. Herein, we found that sorafenib induced extensive acetylation changes towards a more energetic metabolic phenotype. Metabolic adaptation was mediated via acetylation of the Lys-491 (K491) residue of phosphoenolpyruvate carboxykinase isoform 2 (PCK2) (PCK2–K491) and Lys-473 (K473) residue of PCK1 (PCK1–K473) by the lysine acetyltransferase 8 (KAT8), resulting in isoenzyme transition from cytoplasmic PCK1 to mitochondrial PCK2. KAT8-catalyzed PCK2 acetylation at K491 impeded lysosomal degradation to increase the level of PCK2 in resistant cells. PCK2 inhibition in sorafenib-resistant cells significantly reversed drug resistance in vitro and in vivo. High levels of PCK2 predicted a shorter progression-free survival time in patients who received sorafenib treatment. Therefore, acetylation-induced isoenzyme transition from PCK1 to PCK2 contributes to resistance to systemic therapeutic drugs in liver cancer. PCK2 may be an emerging target for delaying tumor recurrence.

Original languageEnglish
Pages (from-to)46-62
Number of pages17
JournalCancer Letters
Volume519
DOIs
StatePublished - Oct 28 2021

Keywords

  • Acetylproteomics
  • Lysine acetyltransferase 8
  • Lysosome-related protein degradation
  • Metabolic adaptation
  • Phosphoenolpyruvate carboxykinase isoform 2
  • Phosphoproteomics
  • Protein acetylation
  • Protein posttranslational modifications
  • Sorafenib resistance

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