PMID- 37788309
OWN - NLM
STAT- MEDLINE
DCOM- 20231005
LR  - 20240404
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 120
IP  - 41
DP  - 2023 Oct 10
TI  - Nuclear VCP drives colorectal cancer progression by promoting fatty acid 
      oxidation.
PG  - e2221653120
LID - 10.1073/pnas.2221653120 [doi]
LID - e2221653120
AB  - Fatty acid oxidation (FAO) fuels many cancers. However, knowledge of pathways 
      that drive FAO in cancer remains unclear. Here, we revealed that 
      valosin-containing protein (VCP) upregulates FAO to promote colorectal cancer 
      growth. Mechanistically, nuclear VCP binds to histone deacetylase 1 (HDAC1) and 
      facilitates its degradation, thus promoting the transcription of FAO genes, 
      including the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A). FAO 
      is an alternative fuel for cancer cells in environments exhibiting limited 
      glucose availability. We observed that a VCP inhibitor blocked the upregulation 
      of FAO activity and CPT1A expression triggered by metformin in colorectal cancer 
      (CRC) cells. Combined VCP inhibitor and metformin prove more effective than 
      either agent alone in culture and in vivo. Our study illustrates the molecular 
      mechanism underlying the regulation of FAO by nuclear VCP and demonstrates the 
      potential therapeutic utility of VCP inhibitor and metformin combination 
      treatment for colorectal cancer.
FAU - Huang, Youwei
AU  - Huang Y
AUID- ORCID: 0000-0001-8350-1991
AD  - Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 
      510632, China.
AD  - Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and 
      Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital 
      Affiliated with Jinan University, Zhuhai 519000, China.
AD  - Biomedical Translational Research Institute, Health Science Center (School of 
      Medicine), Jinan University, Guangzhou 510632, China.
FAU - Wang, Fang
AU  - Wang F
AUID- ORCID: 0009-0008-5160-7909
AD  - Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 
      510632, China.
FAU - Lin, Xi
AU  - Lin X
AD  - Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 
      510632, China.
FAU - Li, Qing
AU  - Li Q
AUID- ORCID: 0009-0006-2192-9929
AD  - Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 
      510632, China.
FAU - Lu, Yuli
AU  - Lu Y
AUID- ORCID: 0009-0008-8514-6602
AD  - Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 
      510632, China.
AD  - Department of Public Health, Shantou Center for Disease Control and Prevention, 
      Shantou 515000, China.
FAU - Zhang, Jiayu
AU  - Zhang J
AUID- ORCID: 0000-0003-1132-1101
AD  - Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital 
      of Sun Yat-sen University, Guangzhou 510655, China.
FAU - Shen, Xi
AU  - Shen X
AUID- ORCID: 0009-0004-8168-1481
AD  - Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 
      510632, China.
FAU - Tan, Jingyi
AU  - Tan J
AUID- ORCID: 0009-0001-8597-6998
AD  - Biomedical Translational Research Institute, Health Science Center (School of 
      Medicine), Jinan University, Guangzhou 510632, China.
FAU - Qin, Zixi
AU  - Qin Z
AUID- ORCID: 0009-0003-1251-8093
AD  - Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 
      510632, China.
FAU - Chen, Jiahong
AU  - Chen J
AUID- ORCID: 0009-0001-5878-1896
AD  - Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 
      510632, China.
AD  - Department of Pathophysiology, School of Basic Medical Sciences, Peking 
      University, Beijing 100191, China.
FAU - Chen, Xueqin
AU  - Chen X
AUID- ORCID: 0009-0003-7358-4211
AD  - Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 
      510632, China.
FAU - Pan, Guopeng
AU  - Pan G
AUID- ORCID: 0009-0001-7059-644X
AD  - Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 
      510632, China.
FAU - Wang, Xiangyu
AU  - Wang X
AUID- ORCID: 0009-0005-4840-4308
AD  - Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 
      510632, China.
FAU - Zeng, Yuequan
AU  - Zeng Y
AUID- ORCID: 0009-0005-2297-1515
AD  - Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 
      510632, China.
FAU - Yang, Shangqi
AU  - Yang S
AD  - Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 
      510632, China.
FAU - Liu, Jun
AU  - Liu J
AUID- ORCID: 0000-0002-8563-7603
AD  - Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 
      510632, China.
FAU - Xing, Fan
AU  - Xing F
AD  - Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong 
      Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, 
      China.
FAU - Li, Kai
AU  - Li K
AUID- ORCID: 0000-0001-6495-352X
AD  - Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital 
      of Sun Yat-sen University, Guangzhou 510655, China.
FAU - Zhang, Haipeng
AU  - Zhang H
AUID- ORCID: 0000-0001-9188-542X
AD  - Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 
      510632, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231003
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - EC 3.6.4.6 (Valosin Containing Protein)
RN  - 0 (Fatty Acids)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
RN  - EC 3.6.4.6 (VCP protein, human)
SB  - IM
MH  - Humans
MH  - Valosin Containing Protein/genetics/metabolism
MH  - Neoplastic Processes
MH  - *Colorectal Neoplasms/drug therapy/genetics/metabolism
MH  - Fatty Acids/metabolism
MH  - *Metformin/pharmacology
MH  - Carnitine O-Palmitoyltransferase/metabolism
MH  - Oxidation-Reduction
PMC - PMC10576098
OTO - NOTNLM
OT  - VCP
OT  - colorectal cancer
OT  - combination therapy
OT  - fatty acid oxidation
OT  - metformin
COIS- The authors declare no competing interest.
EDAT- 2023/10/03 18:43
MHDA- 2023/10/05 06:43
PMCR- 2024/04/03
CRDT- 2023/10/03 14:03
PHST- 2023/10/05 06:43 [medline]
PHST- 2023/10/03 18:43 [pubmed]
PHST- 2023/10/03 14:03 [entrez]
PHST- 2024/04/03 00:00 [pmc-release]
AID - 202221653 [pii]
AID - 10.1073/pnas.2221653120 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2023 Oct 10;120(41):e2221653120. doi: 
      10.1073/pnas.2221653120. Epub 2023 Oct 3.