CELF6 modulates triple-negative breast cancer progression by regulating the stability of FBP1 mRNA

Breast Cancer Res Treat. 2020 Aug;183(1):71-82. doi: 10.1007/s10549-020-05753-9. Epub 2020 Jun 29.

Abstract

Background: Triple-negative breast cancer (TNBC) remains a great challenge in clinical treatment due to a shortage of effective therapeutic targets and acquired chemoresistance. Here, we identified the role of an RNA-binding protein, CUG-BP Elav-like family member 6 (CELF6), in the TNBC development and paclitaxel (PTX) chemoresistance.

Methods: Stable CELF6-overexpressing cell lines were established in BT549 and MDA-MB-231 cells. Cell proliferation was determined using cell counting, two-dimensional colony formation, and MTT assay. Meanwhile, cell migration and cell invasion were detected by Transwell assay. Furthermore, the downstream target gene of CELF6 was identified and the direct interaction was further determined by luciferase reporter assay, immunoprecipitation, and RNA pull-down. Additionally, the PTX resistant cell line was established to determine the role of CELF6 in PTX resistance.

Results: CELF6 overexpression suppressed cell proliferation, cell migration, and cell invasion. Mechanistically, Fructose-Bisphosphatase 1 (FBP1) was identified as the target gene of CELF6 and stabilized by CELF6 via binding 3'UTR. CELF6 overexpression mediated inhibition in TNBC development was dependent on FBP1. Moreover, CELF6 overexpression increased the sensitivity to PTX treatment.

Conclusion: CELF6 functions as a tumor suppressor by upregulating FBP 1 expression via stabilizing its mRNA, and thereby inhibits TNBC progression.

Keywords: CELF6; Chemoresistance; FBP1; Paclitaxel; Triple-negative breast cancer.

MeSH terms

  • 3' Untranslated Regions
  • Antineoplastic Agents, Phytogenic / pharmacology
  • CELF Proteins / physiology*
  • Cell Line, Tumor
  • Cell Movement
  • Disease Progression
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Fructose-Bisphosphatase / antagonists & inhibitors
  • Fructose-Bisphosphatase / genetics
  • Gene Knockdown Techniques
  • Genes, Reporter
  • Humans
  • Neoplasm Invasiveness
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Paclitaxel / pharmacology
  • RNA Stability*
  • RNA, Messenger / metabolism*
  • RNA, Neoplasm / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology
  • Triple Negative Breast Neoplasms / drug therapy
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism*
  • Triple Negative Breast Neoplasms / pathology
  • Up-Regulation

Substances

  • 3' Untranslated Regions
  • Antineoplastic Agents, Phytogenic
  • CELF Proteins
  • CELF6 protein, human
  • Neoplasm Proteins
  • RNA, Messenger
  • RNA, Neoplasm
  • RNA, Small Interfering
  • FBP1 protein, human
  • Fructose-Bisphosphatase
  • Paclitaxel