Fisetin inhibits proliferation of pancreatic adenocarcinoma by inducing DNA damage via RFXAP/KDM4A-dependent histone H3K36 demethylation
Pancreatic adenocarcinoma (PDAC) is an extremely malignant tumor that is associated with low survival rates. Fisetin is a natural flavonoid that shows diverse antitumor effects, including DNA damage, in various cancers. Increasing studies have demonstrated that epigenetic modifications play critical...
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Veröffentlicht in: | Cell death & disease 2020-10, Vol.11 (10), p.893, Article 893 |
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Zusammenfassung: | Pancreatic adenocarcinoma (PDAC) is an extremely malignant tumor that is associated with low survival rates. Fisetin is a natural flavonoid that shows diverse antitumor effects, including DNA damage, in various cancers. Increasing studies have demonstrated that epigenetic modifications play critical roles in DNA-damage response. However, the epigenetic regulation mechanism of fisetin in cancers is hardly studied. RFXAP is a critical transcription factor for MHC II molecules, however, its transcriptional role in PDAC is poorly understood. The anti-PDAC effect of fisetin was measured by CCK-8, flow cytometry, xenograft tumor nude mice model. DNA-damage levels were examined by immunofluorescence. Bioinformatics analysis was used to examine the expression of RFXAP and other genes involved in DNA-damage response. ChIP sequencing was used to explore the transcriptional role of RFXAP. The expression of target gene
KDM4A
was measured by qRT-PCR and western blots.
KDM4A
promoter activity was analyzed using dual-luciferase reporter assay. RFXAP overexpressing or silencing of PDAC cells was used to explore the effect of RFXAP in DNA damage induced by fisetin. We found that fisetin inhibited cell proliferation and induced DNA damage and S-phase arrest in PDAC. Expression of
RFXAP
and other DNA-damage response genes were upregulated by fisetin. We revealed that
RFXAP
expression was relatively low in PDAC and correlated with tumor stage and poor prognosis. Then we explored the transcriptional role of RFXAP and found that RFXAP targeted
KDM4A
, a special demethylase specific for tri- and dimethylated histone H3K36. We found that overexpression of RFXAP upregulated
KDM4A
and attenuated methylation of H3K36, thereby impairing DNA repair and enhancing the DNA damage induced by fisetin, while
RFXAP
silencing showed the opposite effect. We also found the function of fisetin in enhancing the effect of chemotherapy on pancreatic cancer cells. Our findings revealed that fisetin induced DNA damage via RFXAP/KDM4A-dependent histone H3K36 demethylation, thus causing inhibition of proliferation in PDAC. |
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ISSN: | 2041-4889 2041-4889 |
DOI: | 10.1038/s41419-020-03019-2 |