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

doi:10.1016/j.canlet.2021.06.016

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

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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 language	English
Pages (from-to)	46-62
Number of pages	17
Journal	Cancer Letters
Volume	519
DOIs	https://doi.org/10.1016/j.canlet.2021.06.016
State	Published - 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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10.1016/j.canlet.2021.06.016

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@article{110340bd12f1498bad8b98c65b599bb8,

title = "Acetylation-induced PCK isoenzyme transition promotes metabolic adaption of liver cancer to systemic therapy",

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.",

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

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

note = "Funding Information: This work was supported in part by the National Key R & D Program (Nos. 2017ZX10203205-003-001 , 2018YFC1313101 and 2016YGC0901403 to X.H.Z.), the National Natural Science Foundation (Nos. 81872033 and 82073327 to X.H.Z. and Y.L.S.) and the CAMS Innovation Fund for Medical Sciences (Nos. 2016-I2M-1-001, 2017-I2M-3–005 and 2019-I2M-1–003 to X.H.Z. and Y.L.S.) of China. We thank Ms. Xiu Dong, Lijun Yang and Meng Cai for their technical support. Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = oct,

day = "28",

doi = "10.1016/j.canlet.2021.06.016",

language = "English",

volume = "519",

pages = "46--62",

journal = "Cancer Letters",

issn = "0304-3835",

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TY - JOUR

T1 - Acetylation-induced PCK isoenzyme transition promotes metabolic adaption of liver cancer to systemic therapy

AU - Jing, Zongpan

AU - Gao, Jiajia

AU - Li, Jun

AU - Niu, Fangfei

AU - Tian, Lusong

AU - Nan, Peng

AU - Sun, Yan

AU - Xie, Xiufeng

AU - Zhu, Ying

AU - Zhao, Yan

AU - Liu, Fang

AU - Zhou, Lanping

AU - Sun, Yulin

AU - Zhao, Xiaohang

N1 - Funding Information: This work was supported in part by the National Key R & D Program (Nos. 2017ZX10203205-003-001 , 2018YFC1313101 and 2016YGC0901403 to X.H.Z.), the National Natural Science Foundation (Nos. 81872033 and 82073327 to X.H.Z. and Y.L.S.) and the CAMS Innovation Fund for Medical Sciences (Nos. 2016-I2M-1-001, 2017-I2M-3–005 and 2019-I2M-1–003 to X.H.Z. and Y.L.S.) of China. We thank Ms. Xiu Dong, Lijun Yang and Meng Cai for their technical support. Publisher Copyright: © 2021 The Authors

PY - 2021/10/28

Y1 - 2021/10/28

N2 - 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.

AB - 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.

KW - Acetylproteomics

KW - Lysine acetyltransferase 8

KW - Lysosome-related protein degradation

KW - Metabolic adaptation

KW - Phosphoenolpyruvate carboxykinase isoform 2

KW - Phosphoproteomics

KW - Protein acetylation

KW - Protein posttranslational modifications

KW - Sorafenib resistance

UR - http://www.scopus.com/inward/record.url?scp=85110421386&partnerID=8YFLogxK

U2 - 10.1016/j.canlet.2021.06.016

DO - 10.1016/j.canlet.2021.06.016

M3 - Article

C2 - 34166767

AN - SCOPUS:85110421386

VL - 519

SP - 46

EP - 62

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

ER -

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

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