Metabolic perturbation of epigenome by inhibiting S-adenosylhomocysteine hydrolase elicits senescence through DNA damage response in hepatoma cells.
Tumour Biol
; 39(5): 1010428317699117, 2017 May.
Article
de En
| MEDLINE
| ID: mdl-28459194
ABSTRACT
Cellular senescence is a key physiological barrier against tumor and represents an option for therapeutic intervention. One pivotal intracellular stimulus causing senescence is DNA damage response, while the senescence-associated heterochromatin in cancer limits the strength of the DNA damage response to endogenous genotoxic stress or DNA-damaging agents. Therefore, targeting the maintenance of compacted chromatin in cancer cells represents an optional intervention to improve the therapeutic efficacy in cancer treatment. Given a crosstalk between methionine cycle and histone methylation, we hypothesize that pharmacologically disrupting methylation potential, defined as the ratio of cellular S-adenosylmethionine to S-adenosylhomocysteine, could affect the chromatin structures in cancer cells and thus enhance their sensitivity to DNA damage response signaling. Our results showed that 3-deazaneplanocin A, a chemical inhibitor of S-adenosylhomocysteine hydrolase, elicited a typical cellular senescence in hepatoma cells. Therapy-induced senescence by 3-deazaneplanocin A was mediated through p53-p21 pathway and triggered by enhanced ataxia-telangiectasia mutated activation related to chromatin changes. In conclusion, our study demonstrated that metabolic perturbation of chromatin status in oncogene-activated cancers could be an optional intervention to sensitize DNA damage response signaling.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Altération de l'ADN
/
Carcinome hépatocellulaire
/
Voies et réseaux métaboliques
/
Épigénomique
/
Tumeurs du foie
Limites:
Humans
Langue:
En
Journal:
Tumour Biol
Sujet du journal:
NEOPLASIAS
Année:
2017
Type de document:
Article
Pays d'affiliation:
Chine