Deficiency in mammalian STN1 promotes colon cancer development via inhibiting DNA repair

Dinh Duc Nguyen1, Eugene Kim1, Nhat Thong Le2

  • 1Department of Cancer Biology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA.

Science Advances
|May 10, 2023
PubMed

Insights

STN1 deficiency is a newly identified risk factor for colorectal cancer (CRC). This study reveals the STN1-base excision repair (BER) pathway protects colon tissues from oxidative damage, offering insights into CRC suppression.

Area of Science:

  • Genetics
  • Molecular Biology
  • Oncology

Background:

  • Colorectal cancers (CRCs) have high lethality with limited identified genetic risk factors.
  • The CTC1-STN1-TEN1 complex is crucial for genome stability, but its role in cancer is unknown.

Purpose of the Study:

  • To investigate the role of the CTC1-STN1-TEN1 complex, specifically STN1, in colorectal cancer development.
  • To elucidate the molecular mechanisms by which STN1 deficiency contributes to CRC.

Main Methods:

  • Generated an inducible STN1 knockout mouse model.
  • Analyzed CRC tumors for proliferation, apoptosis, DNA damage, and replication stress markers.
  • Assessed DNA glycosylase expression and base excision repair (BER) pathway function.

Main Results:

  • Attenuated CTC1/STN1 expression was observed in CRCs.
  • STN1 deficiency in mice led to increased CRC incidence, tumor size, and tumor load.
  • STN1 deficiency caused enhanced proliferation, reduced apoptosis, elevated DNA damage, and replication stress.
  • STN1 deficiency down-regulated DNA glycosylases, impairing BER and causing oxidative damage accumulation.

Conclusions:

  • STN1 deficiency is identified as a risk factor for colorectal cancer.
  • The STN1-BER axis is implicated in protecting colon tissues from oxidative damage.
  • This study provides novel insights into the tumor-suppressing mechanisms of STN1 in CRC.

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