Curcumin up‐regulates phosphatase and tensin homologue deleted on chromosome 10 through micro RNA ‐mediated control of DNA methylation – a novel mechanism suppressing liver fibrosis

• Published in: The FEBS journal Vol. 281; no. 1; pp. 88 - 103
• Main Authors: Zheng, Jianjian, Wu, Cunzao, Lin, Zhuo, Guo, Yong, Shi, Liang, Dong, Peihong, Lu, Zhongqiu, Gao, Shenmeng, Liao, Yi, Chen, Bicheng, Yu, Fujun
• Format: Journal Article
• Language: English
• Published: 01-01-2014
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.12574

Phosphatase and tensin homologue deleted on chromosome 10 (
PTEN
) has been reported to play a role in the suppression of activated hepatic stellate cells (
HSC
s). Moreover, it has been demonstrated that hypermethylation of the
PTEN
promoter is responsible for the loss of
PTEN
expression during
HSC
activation. Methylation is now established as a fundamental regulator of gene transcription. Micro
RNA
s (mi
RNA
s), which can control gene expression by binding to their target genes for degradation and/or translational repression, were found to be involved in liver fibrosis. However, the mechanism responsible for mi
RNA
‐mediated epigenetic regulation in liver fibrosis still remained unclear. In the present study, curcumin treatment significantly resulted in the inhibition of cell proliferation and an increase in the apoptosis rate through the up‐regulation of
PTEN
associated with a decreased
DNA
methylation level. Only
DNA
methyltransferase 3b (
DNMT
3b) was reduced
in vivo
and
in vitro
after curcumin treatment. Further studies were performed aiming to confirm that the knockdown of
DNMT
3b enhanced the loss of
PTEN
methylation by curcumin. In addition, miR‐29b was involved in the hypomethylation of
PTEN
by curcumin. MiR‐29b not only was increased by curcumin in activated
HSC
s, but also was confirmed to target
DNMT
3b by luciferase activity assays. Curcumin‐mediated
PTEN
up‐regulation,
DNMT
3b down‐regulation and
PTEN
hypomethylation were all attenuated by miR‐29b inhibitor. Collectively, it is demonstrated that curcumin can up‐regulate miR‐29b expression, resulting in
DNMT
3b down‐regulation in
HSC
s and epigenetically‐regulated
PTEN
involved in the suppression of activated
HSC
s. These results indicate that mi
RNA
‐mediated epigenetic regulation may be a novel mechanism suppressing liver fibrosis.