Advanced adenoid cystic carcinoma (ACC) is featured by SWI/SNF chromatin remodeling complex aberrations

J Cancer Res Clin Oncol. 2019 Jan;145(1):201-211. doi: 10.1007/s00432-018-2783-5. Epub 2018 Oct 31.

Abstract

Purpose: Adenoid cystic carcinoma (ACC) is a rare neurotropic cancer with slow progression occurring in salivary glands and less frequently in other body parts. ACC is featured by hyperchromatic nuclei and various mutations in genes encoding chromatin-related machineries. The ACC treatment is mainly limited to the radical surgery and radiotherapy while the chemotherapy remains ineffective. As the knowledge about molecular basis of ACC development is limited, we investigated here the molecular features of this disease.

Patients and methods: This study included 50 patients with ACC. Transcript profiling of available ACC samples vs normal salivary gland tissue, quantitative real-time PCR (qRT-PCR) transcript level measurements and the immunohistochemistry (IHC) for SWI/SNF chromatin remodeling complex (CRC) subunits and androgen receptor on surgery-derived paraffin-embedded samples were performed.

Results: Transcriptomic study followed by Gene Ontology classification indicated alteration of chromatin-related processes, including downregulated transcript levels of main SWI/SNF CRC subunits and elevated expression of BRM ATPase-coding SMARCA2 gene in ACC. Subsequent IHC indicated broad accumulation of BRM ATPase and several SWI/SNF subunits, suggesting affected control of their protein level in ACC. The IHC revealed ectopic, heterogeneous expression of androgen receptor (AR) in some ACC cells.

Conclusions: Our study indicated that ACC features aberrant expression of genes controlling chromatin status and structure. We found that the balance between SWI/SNF classes is moved towards the BRM ATPase-containing complex in ACC. As BRM is known to be involved in chemoresistance in cancer cells, this observation may be the likely explanation for ACC chemoresistance.

Keywords: Adenoid cystic carcinoma; Androgen receptor (AR); Chemoresistance; Progressive disease; SWI/SNF complex.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Adenoid Cystic / genetics
  • Carcinoma, Adenoid Cystic / metabolism
  • Carcinoma, Adenoid Cystic / pathology*
  • Chromatin Assembly and Disassembly*
  • Female
  • Gene Expression Profiling
  • Humans
  • Male
  • Middle Aged
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Androgen / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptome
  • Young Adult

Substances

  • RNA, Messenger
  • Receptors, Androgen
  • SMARCA2 protein, human
  • Transcription Factors