Genome-wide DNA methylation and hydroxymethylation analysis reveal human menstrual blood-derived stem cells inhibit hepatocellular carcinoma growth through oncogenic pathway suppression via regulating 5-hmC in enhancer elements | Stem Cell Research & Therapy | Full Text

Genome-wide DNA methylation and hydroxymethylation analysis reveal human menstrual blood-derived stem cells inhibit hepatocellular carcinoma growth through oncogenic pathway suppression via regulating 5-hmC in enhancer elements | Stem Cell Research & Therapy | Full Text

Genome-wide DNA methylation and hydroxymethylation analysis reveal human menstrual blood-derived stem cells inhibit hepatocellular carcinoma growth through oncogenic pathway suppression via regulating 5-hmC in enhancer elements

• Yichen Wu, 
• Xin Chen, 
• Yongjia Zhao, 
• Yanling Wang, 
• Yifei Li & 
• Charlie Xiang 

Stem Cell Research & Therapy volume 10, Article number: 151 (2019) Cite this article

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Abstract

Background

Epigenetic alteration is an important indicator of crosstalk between cancer cells and surrounding microenvironment components including mesenchymal stem cells (MSC). Human menstrual blood-derived stem cells (MenSCs) are novel source of MSCs which exert suppressive effects on cancers via multiple components of microenvironmental paracrine signaling. However, whether MenSCs play a crucial role in the epigenetic regulation of cancer cells remains unknown.

Methods

Epigenetic alterations of hepatocellular carcinoma (HCC) mediated by MenSCs were examined by immunofluorescence, ELISA, and RT-PCR assays. The suppressive impact of MenSCs on HCC was investigated in vitro using CCK8, apoptosis, wound healing, and invasion assays and in vivo using a xenograft mice model. MeDIP-seq, hMeDIP-seq, and RNA-seq were used to identify the genome-wide pattern of DNA methylation and hydroxymethylation in HCC cells after MenSC therapy.

Results

We show that HCC cells display distinct genome-wide alterations in DNA hydroxymethylation and methylation after MenSC therapy. MenSCs exert an inhibitory effect on HCC growth via regulating 5-hmC and 5-mC abundance in the regulatory regions of oncogenic pathways including PI3K/AKT and MAPK signaling, especially in enhancers and promoters. FOXO3 expression is rescued via reversal of 5-hmC and 5-mC levels in its enhancers and contributes to the activation of downstream apoptosis. Inactivation of the MAPK pathway further disrupts c-myc-mediated epithelial-mesenchymal transitions (EMT). Additionally, chemotherapy resistance-associated genes including ID4 and HMGA1 are suppressed via amending 5-hmC and 5-mC abundance at their regulatory regions. HMGA1 and BYSL might be potential targets for gene-modified MSC therapy.

Conclusions

Our results confirm that MSCs could regulate the epigenetic mechanism of HCC cells and provide a novel concept for a modified MSC strategy or combination therapy with chemotherapeutics based on epigenetics.