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Cancer/testis antigen PIWIL2 suppresses circadian rhythms by regulating the stability and activity of BMAL1 and CLOCK

Yilu Lu1, Xulei Zheng1, Wei Hu1

  • 1Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.

Oncotarget
|September 15, 2017
PubMed

Insights

The cancer/testis antigen PIWIL2 suppresses circadian rhythms in testis and cancer cells by inhibiting the degradation of clock proteins BMAL1 and CLOCK, linking germ cell and tumor development to circadian disruption.

Area of Science:

  • Molecular Biology
  • Chronobiology
  • Cancer Research

Background:

  • Circadian rhythms rely on clock protein feedback loops for regulation.
  • Rhythmic degradation of clock proteins is essential for maintaining circadian oscillations.
  • Circadian rhythms are suppressed during spermatogenesis and disrupted in tumors, with unknown mechanisms.

Purpose of the Study:

  • To investigate the mechanism by which circadian rhythms are suppressed in germ cells and cancer cells.
  • To identify the role of the cancer/testis antigen PIWIL2 in circadian rhythm regulation.

Main Methods:

  • Investigated PIWIL2's interaction with the PI3K-AKT-GSK3β pathway.
  • Analyzed PIWIL2's effect on phosphorylation and degradation of BMAL1 and CLOCK proteins.
  • Examined PIWIL2's binding to E-Box sequences and its impact on transcriptional activity.

Main Results:

  • PIWIL2 activates the PI3K-AKT pathway, leading to GSK3β deactivation.
  • GSK3β-induced phosphorylation and degradation of BMAL1 and CLOCK are suppressed by PIWIL2.
  • PIWIL2 binds to E-Box sequences, negatively regulating clock-controlled gene promoters.

Conclusions:

  • PIWIL2 represses circadian rhythms in both testis and cancer cells.
  • PIWIL2's function provides a molecular link between spermatogenesis, tumorigenesis, and circadian rhythm dysfunction.
Keywords:
GSK3βPIWIL2circadian clockubiquitination

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