EGF-Induced Acetylation of Heterogeneous Nuclear Ribonucleoproteins Is Dependent on KRAS Mutational Status in Colorectal Cancer Cells

PLoS One. 2015 Jun 25;10(6):e0130543. doi: 10.1371/journal.pone.0130543. eCollection 2015.

Abstract

KRAS mutational status is considered a negative predictive marker of the response to anti-EGFR therapies in colorectal cancer (CRC) patients. However, conflicting data exist regarding the variable response to EGFR-targeted therapy. The effects of oncogenic KRAS on downstream targets were studied in cell lines with different KRAS mutations. Cells harboring a single KRASG13D allele showed the most tumorigenic profile, with constitutive activation of the downstream pathway, rendering them EGF-unresponsive. Conversely, KRASA146T cells showed a full EGF-response in terms of signal transduction pathways, cell proliferation, migration or adhesion. Moreover, the global acetylome of CRC cells was also dependent on KRAS mutational status. Several hnRNP family members were identified within the 36 acetylated-proteins. Acetylation status is known to be involved in the modulation of EGF-response. In agreement with results presented herein, hnRNPA1 and L acetylation was induced in response to EGF in KRASA146T cells, whereas acetyl-hnRNPA1 and L levels remained unchanged after growth factor treatment in KRASG13D unresponsive cells. Our results showed that hnRNPs induced-acetylation is dependent on KRAS mutational status. Nevertheless hnRNPs acetylation might also be the point where different oncogenic pathways converge.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Drug Resistance, Neoplasm / genetics
  • Epidermal Growth Factor / antagonists & inhibitors
  • Epidermal Growth Factor / genetics*
  • Gene Expression Regulation, Neoplastic / drug effects
  • HCT116 Cells
  • Heterogeneous-Nuclear Ribonucleoproteins / genetics*
  • Humans
  • Mutation
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Signal Transduction / drug effects

Substances

  • Heterogeneous-Nuclear Ribonucleoproteins
  • KRAS protein, human
  • Epidermal Growth Factor
  • Proto-Oncogene Proteins p21(ras)

Grants and funding

This work was supported in part by grants from Spanish government, Ministerio de Economía y Competitividad and FEDER grants (FIS PI09/02480 and PI12/02767 to AC; FIS PI12/02394 to ERGT and FIS PI12/02110 to GLR) and Generalitat Valenciana (PROMETEO 2013-005 to AC). DR held a fellowship from Ministerio de Ciencia e Innovación (Rio Hortega Program) and from Sociedad Española Oncología Médica (SEOM); MTM is a pre-doctoral fellow from Generalitat Valenciana (Prometeo) and AG is a recipient of postdoctoral fellowship from Spanish Association Against Cancer (AECC, Provincial Board of Baleares).