FUS/TLS is a novel mediator of androgen-dependent cell-cycle progression and prostate cancer growth

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Greg N Brooke1, Rachel L Culley, D Alwyn Dart

  • 1Androgen Signalling Laboratory, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, United Kingdom.

Cancer Research
|December 21, 2010
PubMed

Insights

The RNA-binding protein FUS/TLS (Fused in Ewing's Sarcoma/Translocated in Liposarcoma) acts as a tumor suppressor in prostate cancer. Its downregulation by androgens links androgen receptor signaling to cell-cycle progression, impacting cancer growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Prostate cancer progression relies on the androgen receptor pathway.
  • Understanding androgen-regulated proteins is crucial for combating prostate cancer.
  • The RNA-binding protein FUS/TLS (Fused in Ewing's Sarcoma/Translocated in Liposarcoma) was identified via proteomic screening.

Purpose of the Study:

  • To investigate the role of FUS/TLS in prostate cancer.
  • To elucidate the mechanism by which FUS/TLS regulates cell-cycle progression in response to androgens.
  • To determine the clinical significance of FUS/TLS expression in prostate cancer patients.

Main Methods:

  • Proteomic screening to identify androgen-regulated proteins.
  • In vitro studies involving FUS/TLS overexpression and knockdown in prostate cancer cells.
  • In vivo studies using tumor xenografts to assess FUS/TLS effects on tumor growth.
  • Immunohistochemical analysis of FUS/TLS expression in patient tumors correlated with Gleason grade and clinical outcomes.

Main Results:

  • FUS/TLS is downregulated by androgens and functions as a tumor suppressor.
  • FUS/TLS overexpression inhibits prostate cancer cell growth and induces apoptosis; knockdown increases proliferation.
  • FUS/TLS overexpression in vivo leads to significant tumor regression.
  • FUS/TLS reduces proliferative factors (cyclin D1, Cdk6) and increases antiproliferative factors (p27), promoting cell-cycle arrest.
  • FUS/TLS expression inversely correlates with Gleason grade; higher FUS levels are associated with longer survival and fewer bone metastases.

Conclusions:

  • FUS/TLS is a key link between androgen receptor signaling and cell-cycle progression in prostate cancer.
  • Loss of FUS/TLS expression may contribute to prostate cancer progression and metastasis.
  • FUS/TLS represents a potential therapeutic target for prostate cancer treatment.

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