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SKA1 induces de novo MTX-resistance in osteosarcoma through inhibiting FPGS transcription

Wenxi Yu1, Daliu Min2, Feng Lin1

  • 1Department of Oncology, Affiliated 6th People's Hospital, Shanghai Jiaotong University, China.

The FEBS Journal
|March 10, 2019
PubMed

Insights

Spindle and kinetochore associated complex subunit 1 (SKA1) drives de novo methotrexate resistance in osteosarcoma by downregulating folylpoly-γ-glutamate synthetase (FPGS). Reducing SKA1 restores drug sensitivity, offering a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • De novo methotrexate (MTX)-resistance in osteosarcoma (OS) is a significant challenge with poor patient prognosis.
  • The molecular mechanisms underlying this resistance are not well understood.

Purpose of the Study:

  • To establish a de novo MTX-resistant OS cell line and identify key genes involved in resistance.
  • To elucidate the mechanism by which SKA1 contributes to MTX resistance in OS.

Main Methods:

  • Development of a de novo MTX-resistant OS cell line (SF-86).
  • Gene expression analysis and patient cohort studies (n=95) to correlate SKA1 levels with MTX resistance and survival.
  • Mechanistic studies involving protein-protein interactions (SKA1-RPB3) and chromatin immunoprecipitation (ChIP) assays to investigate FPGS regulation.

Main Results:

  • SKA1 was identified as a candidate gene involved in de novo MTX-resistance.
  • SKA1 overexpression in OS patients correlated significantly with MTX resistance and reduced 5-year survival.
  • SKA1 overexpression downregulated FPGS, a key enzyme for MTX activation, by inhibiting RPB3-mediated transcription of the FPGS gene.
  • Downregulation of SKA1 restored MTX sensitivity in resistant OS cells.

Conclusions:

  • SKA1 is a novel regulator of FPGS and plays a critical role in the development of de novo MTX-resistance in osteosarcoma.
  • Targeting SKA1 may represent a promising therapeutic strategy to overcome MTX resistance in OS patients.
Keywords:
MTXSKA1drug resistanceosteosarcoma

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