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Heat shock factor 1 suppression induces spindle abnormalities and sensitizes cells to antimitotic drugs

Hsiao-Hui Kuo1, Zhi-Rou Su1,2, Jing-Yuan Chuang2

  • 1Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, 115, Taiwan.

Cell Division
|December 19, 2021
PubMed
Abstract

Insights

Heat shock factor 1 (HSF1) transactivation activity is crucial for proper mitotic spindle assembly and cell proliferation. Inhibiting HSF1 enhances mitotic errors and cell death, suggesting therapeutic potential.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Heat shock factor 1 (HSF1) regulates heat shock response and malignant cell transformation.
  • HSF1 controls heat shock protein expression during mitosis and acts as a mitotic regulator.
  • Previous studies suggest HSF1's role in chromosome segregation during mitosis.

Purpose of the Study:

  • To investigate if HSF1's transactivation activity is essential for mitotic spindle assembly.
  • To explore the role of HSF1 in maintaining spindle integrity during cell division.
  • To evaluate the potential of targeting HSF1 transactivation for cancer therapy.

Main Methods:

  • Inhibition of HSF1 transactivation using KRIBB11 and CCT251263 during mitosis.
  • Assessment of mitotic spindle abnormalities and microtubule reassembly after nocodazole treatment.
  • HSF1 depletion via siRNA and rescue experiments with wild-type and mutant HSF1 constructs.
  • Overexpression of HSP70 to assess its role in mitigating HSF1 depletion effects.

Main Results:

  • HSF1 phosphorylation at S326 and its transactivation activity increase during mitosis.
  • Inhibition of HSF1 transactivation leads to abnormal mitotic spindles and impaired microtubule aster formation.
  • HSF1 depletion causes mitotic spindle assembly defects, reducing cell proliferation and anchorage-independent growth (AIG).
  • Ectopic expression of wild-type or constitutively active HSF1 rescues these defects, unlike S326A or dominant-negative mutants.
  • Overexpression of HSP70 partially rescues HSF1 depletion-induced spindle abnormalities.
  • Inhibition of HSF1 transactivation potentiates spindle defects and cell death induced by anti-mitosis drugs.

Conclusions:

  • Increased HSF1 transactivation activity during mitosis is necessary for accurate spindle assembly and cell viability.
  • HSF1 plays a role in supporting cell proliferation and AIG by maintaining spindle integrity.
  • Targeting HSF1 transactivation may enhance the efficacy of anti-mitosis drugs by increasing mitotic errors and cell death.
Keywords:
Cell deathHSF1Spindle assembly

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