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SOX9 Transcriptionally Regulates mTOR-Induced Proliferation of Basal Cell Carcinomas

Arianna L Kim1, Jung Ho Back1, Sandeep C Chaudhary2

  • 1Department of Dermatology, Columbia University Medical Center, New York, New York, USA.

The Journal of Investigative Dermatology
|March 19, 2018
PubMed

Insights

Targeting the SOX9-mTOR axis offers a new strategy for basal cell carcinoma (BCC) treatment. This pathway bypasses current therapies, potentially improving outcomes for patients with basal cell nevus syndrome.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Current smoothened targeted therapies for basal cell nevus syndrome (BCNS) face challenges with tumor recurrence and resistance.
  • Novel therapeutic strategies targeting downstream components of the Hedgehog pathway are needed for improved efficacy and therapeutic index.

Purpose of the Study:

  • To investigate the role of Sry-related high mobility group box 9 (SOX9) in basal cell carcinoma (BCC) growth.
  • To elucidate the mechanistic link between the Hedgehog and mammalian target of rapamycin (mTOR) pathways in BCC.
  • To evaluate the SOX9-mTOR axis as a potential therapeutic target downstream of smoothened.

Main Methods:

  • Sequence motif analysis identified SOX9-responsive elements in the mTOR promoter.
  • SOX9 knockdown and smoothened inhibition (itraconazole, vismodegib) were performed in murine BCC cells.
  • mTOR expression, downstream target phosphorylation, and cellular proliferation were assessed.
  • Pharmacologic mTOR inhibition with rapamycin was tested in a UV-induced BCC mouse model (Ptch1+/-/SKH-1).

Main Results:

  • SOX9 was found to occupy and induce transcriptional activity of the mTOR promoter in murine BCC cells.
  • SOX9 knockdown and smoothened inhibition reduced mTOR expression and downstream signaling, decreasing BCC cell proliferation.
  • Rapamycin suppressed UV-induced BCC growth in a mouse model mimicking BCNS.
  • Demonstrated a direct mechanistic link between Hedgehog and mTOR pathways driving BCC growth via SOX9.

Conclusions:

  • Hedgehog signaling converges on mTOR through SOX9 in BCC.
  • The SOX9-mTOR axis represents a viable therapeutic target downstream of smoothened.
  • Targeting this axis could enhance tumor elimination in patients with BCC and BCNS.

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