The Transcriptional Coactivator, ALL1-Fused Gene From Chromosome 9, Simultaneously Sustains Hypoxia Tolerance and Metabolic Advantages in Liver Cancer.
Animals
Carcinoma, Hepatocellular
/ genetics
Cell Line, Tumor
Disease Progression
Epigenesis, Genetic
Glycolysis
/ genetics
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
/ genetics
Liver Neoplasms
/ genetics
Mice
Mice, Knockout
Nuclear Proteins
/ genetics
Proto-Oncogene Proteins c-met
/ genetics
Proto-Oncogene Proteins c-myc
/ genetics
Tumor Hypoxia
/ genetics
Tumor Microenvironment
beta Catenin
/ genetics
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
revised:
21
03
2021
received:
13
10
2020
accepted:
09
04
2021
pubmed:
1
5
2021
medline:
11
1
2022
entrez:
30
4
2021
Statut:
ppublish
Résumé
Proteins that recognize epigenetic modifications function as mediators to interpret epigenetic codes. Hypoxia response and metabolic rewiring are two major events during cancer progression. However, whether and how the epigenetic regulator integrates hypoxia response and metabolism together remain open for study. We data mined the clinical association of 33 histone lysine acetylation reader proteins with liver cancer and found that ALL1-fused gene from chromosome 9 (AF9) is up-regulated in cancer and correlates with tumor stage and poor prognosis. Conditional deletion of Af9 in mouse liver resulted in decreased tumor formation induced by c-MET proto-oncogene/β-catenin. Loss of AF9 heavily impaired cell proliferation and completely blocked solid tumor formation. We further discovered that AF9 formed a positive feedback circuit with hypoxia-inducible factor 1 alpha (HIF1α) and also stabilized MYC proto-oncogene (cMyc). Mechanically, AF9 interacted with HIF1α and targeted HIF1A promoter whereas AF9 recognized cMyc acetylation at K148, protected cMyc phosphorylation at S62, and then stabilized cMyc, which, in turn, up-regulates phosphofructokinase, platelet expression. Otherwise, knockout of Af9 in mouse hepatocytes increased the infiltration of CD8 AF9 is up-regulated to promote gene expression of hypoxia tolerance and glycolysis by simultaneously forming a complex with HIF1α and recognizing acetylated cMyc. Our results establish the oncogenic role of AF9 in human liver cancer, which could be a potential target for designing drugs against liver cancer.
Sections du résumé
BACKGROUND AND AIMS
Proteins that recognize epigenetic modifications function as mediators to interpret epigenetic codes. Hypoxia response and metabolic rewiring are two major events during cancer progression. However, whether and how the epigenetic regulator integrates hypoxia response and metabolism together remain open for study.
APPROACH AND RESULTS
We data mined the clinical association of 33 histone lysine acetylation reader proteins with liver cancer and found that ALL1-fused gene from chromosome 9 (AF9) is up-regulated in cancer and correlates with tumor stage and poor prognosis. Conditional deletion of Af9 in mouse liver resulted in decreased tumor formation induced by c-MET proto-oncogene/β-catenin. Loss of AF9 heavily impaired cell proliferation and completely blocked solid tumor formation. We further discovered that AF9 formed a positive feedback circuit with hypoxia-inducible factor 1 alpha (HIF1α) and also stabilized MYC proto-oncogene (cMyc). Mechanically, AF9 interacted with HIF1α and targeted HIF1A promoter whereas AF9 recognized cMyc acetylation at K148, protected cMyc phosphorylation at S62, and then stabilized cMyc, which, in turn, up-regulates phosphofructokinase, platelet expression. Otherwise, knockout of Af9 in mouse hepatocytes increased the infiltration of CD8
CONCLUSIONS
AF9 is up-regulated to promote gene expression of hypoxia tolerance and glycolysis by simultaneously forming a complex with HIF1α and recognizing acetylated cMyc. Our results establish the oncogenic role of AF9 in human liver cancer, which could be a potential target for designing drugs against liver cancer.
Substances chimiques
Hypoxia-Inducible Factor 1, alpha Subunit
0
MLLT3 protein, human
0
Mllt3 protein, mouse
0
Nuclear Proteins
0
Proto-Oncogene Proteins c-myc
0
beta Catenin
0
Proto-Oncogene Proteins c-met
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1952-1970Informations de copyright
© 2021 by the American Association for the Study of Liver Diseases.
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