Expression of GALNT8 and O-glycosylation of BMP receptor 1A suppress breast cancer cell proliferation by upregulating ERα levels

Biochim Biophys Acta Gen Subj. 2022 Jan;1866(1):130046. doi: 10.1016/j.bbagen.2021.130046. Epub 2021 Oct 29.

Abstract

Background: Mucin-type O-glycosylation is one of the most abundant types of O-glycosylation and plays important roles in various human carcinomas, including breast cancer. A large family of polypeptide N-acetyl-α-galactosaminyltransferases (GALNTs) initiate and define sites of mucin-type O-glycosylation. However, the specific mechanisms underlying GALNT8 expression and its roles in tumorigenesis remain poorly characterized.

Methods: GALNT8 expression was assessed in 140 breast cancer patients. Immunofluorescence, immunoprecipitation, lectin blot and quantitative real-time PCR were used to investigate the expression of GALNT8 and its role in regulating estrogen receptor α (ERα) via bone morphogenetic protein (BMP) signaling.

Results: The expression of GALNT8 was associated with breast cancer patient survival. GALNT8 downregulation was associated with a reduction in ERα levels, while GALNT8 overexpression elevated the transcription and protein levels of ERα and suppressed colony formation, suggesting an important role of GALNT8 in cancer cell proliferation. Conversely, GALNT8 knockdown led to the inhibition of BMP/SMAD/RUNX2 axis, which decreased ERα transcription. Further analysis suggested that BMP receptor 1A (BMPR1A) was O-GalNAcylated. Sites mutation of BMPR1A indicated that Thr137 and Ser37/Ser39/Ser44/Thr49 of BMPR1A were the main O-glycosylation sites. Although we cannot exclude the indirect effect of GALNT8, our results demonstrated that the expression of GALNT8 and O-glycosylation of BMPR1A play key roles in regulating the activity of BMP/SMAD/RUNX2 signaling and ERα expression.

Conclusion: These findings suggest that GALNT8 expression and abnormal O-GalNAcylation of BMPR1A increase ERα expression and suppress breast cancer cell proliferation by modulating the BMP signaling pathway.

General significance: Our results identify the involvement of GALNT8 in regulating ERα expression.

Keywords: BMP type I receptor; Breast cancer; ERα; GALNT8; O- GalNAcylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Morphogenetic Protein 1 / metabolism
  • Bone Morphogenetic Protein Receptors / genetics
  • Bone Morphogenetic Protein Receptors / metabolism
  • Bone Morphogenetic Protein Receptors, Type I / genetics
  • Bone Morphogenetic Protein Receptors, Type I / metabolism*
  • Breast Neoplasms / metabolism
  • Carcinogenesis / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Core Binding Factor Alpha 1 Subunit
  • Databases, Genetic
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Estrogens / metabolism
  • Female
  • Gene Expression / genetics
  • Glycosylation
  • Humans
  • Mucin-1
  • N-Acetylgalactosaminyltransferases / genetics*
  • N-Acetylgalactosaminyltransferases / metabolism
  • Polypeptide N-acetylgalactosaminyltransferase
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Signal Transduction
  • Transcriptome / genetics

Substances

  • Core Binding Factor Alpha 1 Subunit
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Estrogens
  • MUC1 protein, human
  • Mucin-1
  • RUNX2 protein, human
  • Receptors, Estrogen
  • N-Acetylgalactosaminyltransferases
  • BMPR1A protein, human
  • Bone Morphogenetic Protein Receptors
  • Bone Morphogenetic Protein Receptors, Type I
  • BMP1 protein, human
  • Bone Morphogenetic Protein 1