CREB-binding protein regulates lung cancer growth by targeting MAPK and CPSF4 signaling pathway

Mol Oncol. 2016 Feb;10(2):317-29. doi: 10.1016/j.molonc.2015.10.015. Epub 2015 Nov 5.

Abstract

CBP (CREB-binding protein) is a transcriptional co-activator which possesses HAT (histone acetyltransferases) activity and participates in many biological processes, including embryonic development, growth control and homeostasis. However, its roles and the underlying mechanisms in the regulation of carcinogenesis and tumor development remain largely unknown. Here we investigated the molecular mechanisms and potential targets of CBP involved in tumor growth and survival in lung cancer cells. Elevated expression of CBP was detected in lung cancer cells and tumor tissues compared to the normal lung cells and tissues. Knockdown of CBP by siRNA or inhibition of its HAT activity using specific chemical inhibitor effectively suppressed cell proliferation, migration and colony formation and induced apoptosis in lung cancer cells by inhibiting MAPK and activating cytochrome C/caspase-dependent signaling pathways. Co-immunoprecipitation and immunofluorescence analyses revealed the co-localization and interaction between CBP and CPSF4 (cleavage and polyadenylation specific factor 4) proteins in lung cancer cells. Knockdown of CPSF4 inhibited hTERT transcription and cell growth induced by CBP, and vice versa, demonstrating the synergetic effect of CBP and CPSF4 in the regulation of lung cancer cell growth and survival. Moreover, we found that high expression of both CBP and CPSF4 predicted a poor prognosis in the patients with lung adenocarcinomas. Collectively, our results indicate that CBP regulates lung cancer growth by targeting MAPK and CPSF4 signaling pathways.

Keywords: CBP; CPSF4; Lung cancer; hTERT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Adenocarcinoma of Lung
  • Apoptosis
  • CREB-Binding Protein / genetics
  • CREB-Binding Protein / metabolism*
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cleavage And Polyadenylation Specificity Factor / chemistry
  • Cleavage And Polyadenylation Specificity Factor / metabolism*
  • Cytochromes c / metabolism
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Histone Acetyltransferases / antagonists & inhibitors
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism*
  • Humans
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • MAP Kinase Signaling System*
  • Prognosis
  • RNA, Small Interfering / metabolism
  • Telomerase / metabolism*

Substances

  • CPSF4 protein, human
  • Cleavage And Polyadenylation Specificity Factor
  • RNA, Small Interfering
  • Cytochromes c
  • CREB-Binding Protein
  • CREBBP protein, human
  • Histone Acetyltransferases
  • TERT protein, human
  • Telomerase
  • Caspases