PMID- 37144836
OWN - NLM
STAT- MEDLINE
DCOM- 20230717
LR  - 20231116
IS  - 1098-2744 (Electronic)
IS  - 0899-1987 (Print)
IS  - 0899-1987 (Linking)
VI  - 62
IP  - 8
DP  - 2023 Aug
TI  - Histone deacetylase inhibitor belinostat regulates metabolic reprogramming in 
      killing KRAS-mutant human lung cancer cells.
PG  - 1136-1146
LID - 10.1002/mc.23551 [doi]
AB  - Kirsten rat sarcoma virus (KRAS) oncogene, found in 20%-25% of lung cancer 
      patients, potentially regulates metabolic reprogramming and redox status during 
      tumorigenesis. Histone deacetylase (HDAC) inhibitors have been investigated for 
      treating KRAS-mutant lung cancer. In the current study, we investigate the effect 
      of HDAC inhibitor (HDACi) belinostat at clinically relevant concentration on 
      nuclear factor erythroid 2-related factor 2 (NRF2) and mitochondrial metabolism 
      for the treatment of KRAS-mutant human lung cancer. LC-MS metabolomic study of 
      belinostat on mitochondrial metabolism was performed in G12C KRAS-mutant H358 
      non-small cell lung cancer cells. Furthermore, l-methionine (methyl-(13) C) 
      isotope tracer was used to explore the effect of belinostat on one-carbon 
      metabolism. Bioinformatic analyses of metabolomic data were performed to identify 
      the pattern of significantly regulated metabolites. To study the effect of 
      belinostat on redox signaling ARE-NRF2 pathway, luciferase reporter activity 
      assay was done in stably transfected HepG2-C8 cells (containing 
      pARE-TI-luciferase construct), followed by qPCR analysis of NRF2 and its target 
      gene in H358 cells, which was further confirmed in G12S KRAS-mutant A549 cells. 
      Metabolomic study reveals significantly altered metabolites related to redox 
      homeostasis, including tricarboxylic acid (TCA) cycle metabolites (citrate, 
      aconitate, fumarate, malate, and alpha-ketoglutarate); urea cycle metabolites 
      (Arginine, ornithine, argino-succinate, aspartate, and fumarate); and 
      antioxidative glutathione metabolism pathway (GSH/GSSG and NAD/NADH ratio) after 
      belinostat treatment. (13) C stable isotope labeling data indicates potential 
      role of belinostat in creatine biosynthesis via methylation of guanidinoacetate. 
      Moreover, belinostat downregulated the expression of NRF2 and its target gene 
      NAD(P)H:quinone oxidoreductase 1 (NQO1), indicating anticancer effect of 
      belinostat is mediated, potentially via Nrf2-regulated glutathione pathway. 
      Another HDACi panobinostat also showed potential anticancer effect in both H358 
      and A549 cells via Nrf2 pathway. In summary, belinostat is effective in killing 
      KRAS-mutant human lung cancer cells by regulating mitochondrial metabolism which 
      could be used as biomarkers for preclinical and clinical studies.
CI  - (c) 2023 Wiley Periodicals LLC.
FAU - Peter, Rebecca M
AU  - Peter RM
AD  - Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, 
      Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA.
AD  - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State 
      University of New Jersey, Piscataway, New Jersey, USA.
FAU - Sarwar, Md Shahid
AU  - Sarwar MS
AD  - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State 
      University of New Jersey, Piscataway, New Jersey, USA.
FAU - Mostafa, Sarah Z
AU  - Mostafa SZ
AD  - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State 
      University of New Jersey, Piscataway, New Jersey, USA.
FAU - Wang, Yujue
AU  - Wang Y
AD  - Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, New 
      Brunswick, New Jersey, USA.
AD  - Department of Medicine, Rutgers-Robert Wood Johnson Medical School, New 
      Brunswick, New Jersey, USA.
FAU - Su, Xiaoyang
AU  - Su X
AD  - Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, New 
      Brunswick, New Jersey, USA.
AD  - Department of Medicine, Rutgers-Robert Wood Johnson Medical School, New 
      Brunswick, New Jersey, USA.
FAU - Kong, Ah-Ng
AU  - Kong AN
AUID- ORCID: 0000-0002-9273-4217
AD  - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State 
      University of New Jersey, Piscataway, New Jersey, USA.
LA  - eng
GR  - P30 ES005022/ES/NIEHS NIH HHS/United States
PT  - Journal Article
DEP - 20230505
PL  - United States
TA  - Mol Carcinog
JT  - Molecular carcinogenesis
JID - 8811105
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - F4H96P17NZ (belinostat)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0U46U6E8UK (NAD)
RN  - GAN16C9B8O (Glutathione)
RN  - 0 (KRAS protein, human)
SB  - IM
MH  - Humans
MH  - Histone Deacetylase Inhibitors/pharmacology
MH  - *Lung Neoplasms/drug therapy/genetics
MH  - Proto-Oncogene Proteins p21(ras)/genetics/metabolism
MH  - *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics
MH  - NF-E2-Related Factor 2/metabolism
MH  - NAD/metabolism
MH  - Glutathione/metabolism
PMC - PMC10524423
MID - NIHMS1903069
OTO - NOTNLM
OT  - HDAC inhibitor
OT  - KRAS mutation
OT  - NRF2
OT  - lung cancer
OT  - mitochondrial metabolism
COIS- Conflict of Interest The authors declare no conflict of interest.
EDAT- 2023/05/05 12:42
MHDA- 2023/07/17 06:42
PMCR- 2024/08/01
CRDT- 2023/05/05 08:33
PHST- 2023/03/29 00:00 [revised]
PHST- 2022/09/30 00:00 [received]
PHST- 2023/04/18 00:00 [accepted]
PHST- 2024/08/01 00:00 [pmc-release]
PHST- 2023/07/17 06:42 [medline]
PHST- 2023/05/05 12:42 [pubmed]
PHST- 2023/05/05 08:33 [entrez]
AID - 10.1002/mc.23551 [doi]
PST - ppublish
SO  - Mol Carcinog. 2023 Aug;62(8):1136-1146. doi: 10.1002/mc.23551. Epub 2023 May 5.