miR-124 and miR-506 inhibit colorectal cancer progression by targeting DNMT3B and DNMT1

Zhiheng Chen; Shaojun Liu; Li Tian; Minghao Wu; Feiyan Ai; Wuliang Tang; Lian Zhao; Juan Ding; Liyang Zhang; Anliu Tang

doi:10.18632/oncotarget.5709

miR-124 and miR-506 inhibit colorectal cancer progression by targeting DNMT3B and DNMT1

Oncotarget. 2015 Nov 10;6(35):38139-50. doi: 10.18632/oncotarget.5709.

Authors

Zhiheng Chen¹, Shaojun Liu², Li Tian², Minghao Wu³, Feiyan Ai^{2

4}, Wuliang Tang², Lian Zhao^{2

4}, Juan Ding⁵, Liyang Zhang⁶, Anliu Tang^{2

4}

Affiliations

¹ Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
² Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
³ Department of Gastroenterology, The Hunan Provincial People's Hospital, Changsha, Hunan, China.
⁴ Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China.
⁵ Department of Oncology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁶ Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Abstract

miR-124 and miR-506 are reportedly down-regulated and associated with tumor progression in many cancers, but little is known about their intrinsic regulatory mechanisms in colorectal cancer (CRC). In this study, we found that the miR-124 and miR-506 levels were significantly lower in human CRC tissues than in controls, as indicated by qRT-PCR and in situ hybridization histochemistry. We also found that the overexpression of miR-124 or miR-506 inhibited tumor cell progression and increased sensitivity to chemotherapy in vitro. Increased miR-124 or miR-506 expression also inhibited tumor cell proliferation and invasion in vivo. Luciferase reporter assays and western blotting were used to determine the association between miR-124, miR-506 and their target genes, DNMTs. We further identified that miR-124 and miR-506 directly targeted DNMT3B and indirectly targeted DNMT1. The overexpression of miR-124 and miR-506 reduced global DNA methylation and restored the expression of E-cadherin, MGMT and P16. In conclusion, our data showed that miR-124 and miR-506 inhibit progression and increase sensitivity to chemotherapy by targeting DNMT3B and DNMT1 in CRC. These findings may provide novel avenues for the development of targeted therapies.

Keywords: DNMT1; DNMT3B; colorectal cancer; miR-124; miR-506.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD
Antineoplastic Agents / pharmacology
Cadherins / genetics
Cadherins / metabolism
Cell Movement
Cell Proliferation
Colorectal Neoplasms / drug therapy
Colorectal Neoplasms / enzymology*
Colorectal Neoplasms / genetics
Colorectal Neoplasms / pathology
Cyclin-Dependent Kinase Inhibitor p16 / genetics
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases / genetics
DNA (Cytosine-5-)-Methyltransferases / metabolism*
DNA Methylation
DNA Methyltransferase 3B
DNA Modification Methylases / genetics
DNA Modification Methylases / metabolism
DNA Repair Enzymes / genetics
DNA Repair Enzymes / metabolism
Disease Progression
Dose-Response Relationship, Drug
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Genes, Reporter
HCT116 Cells
Humans
Mice, Inbred BALB C
Mice, Nude
MicroRNAs / genetics
MicroRNAs / metabolism*
Neoplasm Invasiveness
Signal Transduction
Time Factors
Transfection
Tumor Burden
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism
Xenograft Model Antitumor Assays

Substances

Antigens, CD
Antineoplastic Agents
CDH1 protein, human
Cadherins
Cyclin-Dependent Kinase Inhibitor p16
MIRN124 microRNA, human
MIRN506 microRNA, human
MicroRNAs
Tumor Suppressor Proteins
DNA Modification Methylases
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases
DNMT1 protein, human
Dnmt1 protein, mouse
MGMT protein, human
DNA Repair Enzymes