Curcumin inhibits growth of human breast cancer cells through demethylation of DLC1 promoter

Mol Cell Biochem. 2017 Jan;425(1-2):47-58. doi: 10.1007/s11010-016-2861-4. Epub 2016 Nov 10.

Abstract

The heterogeneity of breast cancer makes it a challenging solid tumor to diagnose and treat. A tumor suppressor Deleted in Liver Cancer 1 (DLC1) has been reported to be down-regulated or even silenced in several kinds of cancer including breast cancer. Curcumin has been reported to modulate the growth of tumor cells through regulation of multiple cell signaling pathways and modulate epigenetic changes by CpG demethylation of many tumor suppressor genes. This study was designed to investigate the effect of curcumin on the expression of Deleted in Liver Cancer 1 (DLC1) in human breast cancer cell line MDA-MB-361 and the underlying mechanism in vitro and in vivo. Curcumin induced DLC1 expression in a dose-dependent manner. In curcumin-treated cells, methylation of DLC1 promoter was reduced and active forms of RhoA and Cdc42 were also decreased. DLC1 expression was closely related to tumor cell growth, demonstrated by Ki67 staining. Curcumin inhibited DNA methyltransferase 1 expression through down-regulation of transcription factor Sp1. Consistent with the in vitro data, in vivo administration of curcumin inhibited the growth of implanted MDA-MB-361 cells and induced DLC1 expression in tumor tissue. In MDA-MB-361 cells, curcumin down-regulates the expression of Sp1 to inhibit the expression of DNA methyltransferase 1, thus subsequently reducing hypermethylation of DLC1 promoter to induce DLC1 expression.

Keywords: Breast cancer; Curcumin; DLC1; DNA methylation.

MeSH terms

  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Curcumin / pharmacology*
  • DNA Methylation / drug effects*
  • DNA, Neoplasm / genetics
  • DNA, Neoplasm / metabolism*
  • Female
  • GTPase-Activating Proteins / biosynthesis*
  • GTPase-Activating Proteins / genetics
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Promoter Regions, Genetic*
  • Tumor Suppressor Proteins / biosynthesis*
  • Tumor Suppressor Proteins / genetics

Substances

  • DLC1 protein, human
  • DNA, Neoplasm
  • GTPase-Activating Proteins
  • Tumor Suppressor Proteins
  • Curcumin