SALL4 as an Epithelial-Mesenchymal Transition and Drug Resistance Inducer Through the Regulation of c-Myc in Endometrial Cancer

PLoS One. 2015 Sep 25;10(9):e0138515. doi: 10.1371/journal.pone.0138515. eCollection 2015.


SALL4 plays important roles in the development and progression of many cancers. However, the role and molecular mechanism of SALL4 in endometrial cancer remain elusive. In the present research, we have demonstrated that the expression of SALL4 was upregulated in endometrial cancer and correlated positively with tumor stage, metastases and poor survival of patients. The overexpression of SALL4 promoted the invasiveness in endometrial cancer cells, as indicated by the upregulation of mesenchymal cell marker N-cadherin and downregulation of the epithelial marker E-cadherin, and invasion assays in vitro. Additionally, there was also an increase in drug resistance in these cell models due to the upregulation of ATP-binding cassette multidrug transporter ABCB1 expression. Moreover, we also found that ABCB1 was critical for SALL4-induced drug resistance. In contrast, SALL4 knockdown restored drug sensitivity, reversed EMT, diminished cell metastasis and suppressed the downregulation of E-cadherin and the upregulation of N-cadherin and ABCB1. Furthermore, we showed that SALL4 upregulated c-Myc expression and c-Myc was a direct target for SALL4 by ChIP assay, depletion of c-Myc with siRNA abolished the SALL4-induced downregulation of E-cadherin, upregulation of N-cadherin and ABCB1, suggesting that c-Myc was a downstream target for SALL4 and required for SALL4-induced EMT, invasion and drugs resistance in endometrial cancer cells. These results indicated that SALL4 could induce EMT and resistance to antineoplastic drugs through the regulation of c-Myc. SALL4 and c-Myc may be novel therapeutic targets for endometrial cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Carcinoma, Endometrioid / genetics*
  • Carcinoma, Endometrioid / mortality
  • Carcinoma, Endometrioid / pathology
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Drug Resistance, Neoplasm / genetics*
  • Endometrial Neoplasms / genetics*
  • Endometrial Neoplasms / mortality
  • Endometrial Neoplasms / pathology
  • Epithelial-Mesenchymal Transition / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Middle Aged
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA, Small Interfering / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Tumor Cells, Cultured


  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • SALL4 protein, human
  • Transcription Factors

Grant support

This project was supported by grants from the National Natural Science Foundation of China (NSFC No. 81172478). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.