Cleavage and polyadenylation specific factor 4 promotes colon cancer progression by transcriptionally activating hTERT

Biochim Biophys Acta Mol Cell Res. 2019 Oct;1866(10):1533-1543. doi: 10.1016/j.bbamcr.2019.07.001. Epub 2019 Jul 10.

Abstract

CPSF4 was identified as a crucial tumorigenic factor in lung cancer development. However, its precise function and the underlying molecular mechanisms in colon cancer progression remain completely unknown. Here, we demonstrate CPSF4 was highly expressed in human colon cancer cells and tissues. Its knockdown inhibited colorectal cancer progression in vitro, including cell proliferation, migration, invasion and stemness maintenance. In contrast, the ectopic overexpression of CPSF4 had the opposite effects in vitro and in vivo. Further mechanistic studies demonstrated that CPSF4 facilitated colorectal tumorigenesis and development partially through transcriptionally regulating hTERT expression by cooperating with NF-kB1 and co-anchoring at hTERT promoter -321 to -234 fragment. In addition, clinical samples analysis indicated that CPSF4 expression was positively correlated with hTERT, and the simultaneously high expression of CPSF4 and hTERT predicted poor patient outcome. Overall, our findings established CPSF4 as a pro-tumorigenic factor in colorectal cancer progression, and suggested that targeting CPSF4-hTERT axis may represent a promising therapeutic strategy in colon cancer treatment.

Keywords: CPSF4; Colorectal cancer; hTERT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle
  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cell Survival
  • Cleavage And Polyadenylation Specificity Factor / genetics
  • Cleavage And Polyadenylation Specificity Factor / metabolism*
  • Colonic Neoplasms / metabolism*
  • Disease Models, Animal
  • Disease Progression*
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Peptide Fragments / metabolism
  • Promoter Regions, Genetic
  • Telomerase / metabolism
  • mRNA Cleavage and Polyadenylation Factors / genetics
  • mRNA Cleavage and Polyadenylation Factors / metabolism*

Substances

  • Cleavage And Polyadenylation Specificity Factor
  • Peptide Fragments
  • mRNA Cleavage and Polyadenylation Factors
  • Telomerase