HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients

Oncotarget. 2015 Mar 20;6(8):6076-91. doi: 10.18632/oncotarget.3475.

Abstract

Human breast tumors harbor supernumerary centrosomes in almost 80% of tumor cells. Although amplified centrosomes compromise cell viability via multipolar spindles resulting in death-inducing aneuploidy, cancer cells tend to cluster extra centrosomes during mitosis. As a result cancer cells display bipolar spindle phenotypes to maintain a tolerable level of aneuploidy, an edge to their survival. HSET/KifC1, a kinesin-like minus-end directed microtubule motor has recently found fame as a crucial centrosome clustering molecule. Here we show that HSET promotes tumor progression via mechanisms independent of centrosome clustering. We found that HSET is overexpressed in breast carcinomas wherein nuclear HSET accumulation correlated with histological grade and predicted poor progression-free and overall survival. In addition, deregulated HSET protein expression was associated with gene amplification and/or translocation. Our data provide compelling evidence that HSET overexpression is pro-proliferative, promotes clonogenic-survival and enhances cell-cycle kinetics through G2 and M-phases. Importantly, HSET co-immunoprecipitates with survivin, and its overexpression protects survivin from proteasome-mediated degradation, resulting in its increased steady-state levels. We provide the first evidence of centrosome clustering-independent activities of HSET that fuel tumor progression and firmly establish that HSET can serve both as a potential prognostic biomarker and as a valuable cancer-selective therapeutic target.

Keywords: HSET; cell-cycle kinetics; centrosome clustering; microtubule motor; tumor progression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aneuploidy
  • Biomarkers, Tumor / biosynthesis
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Centrosome / metabolism*
  • Centrosome / pathology
  • Disease Progression
  • Female
  • HeLa Cells
  • Humans
  • Inhibitor of Apoptosis Proteins / metabolism
  • Kinesin / biosynthesis*
  • Microtubules / metabolism
  • Neoplasm Grading
  • Survivin
  • Transfection
  • Up-Regulation

Substances

  • BIRC5 protein, human
  • Biomarkers, Tumor
  • Inhibitor of Apoptosis Proteins
  • KIFC1 protein, human
  • Survivin
  • Kinesin