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

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.

The overexpression of KIFC1 was associated with the proliferation and prognosis of non-small cell lung cancer

“…KIFC1 involves the growth of tumor and prognosis (18)(19)(20)(21)32), but these were based on clinical specimens. Our experiment is validated at a cellular level for the first time and the further explore the mechanisms was also first expounded.…”

Amplified centrosomes may underlie aggressive disease course in pancreatic ductal adenocarcinoma

“…Protein lysates were prepared and immunoblotting was performed as described earlier. 19 Polyacrylamide gel electrophoresis was used to resolve the proteins, which were transferred onto polyvinylidene fluoride membranes (Millipore). The Pierce ECL chemiluminescence detection kit (Thermo Scientific) was used to visualize the immune-reactive bands.…”

KIFC1: a promising chemotherapy target for cancer treatment?

“…It is reported that KIFC1 is abundantly and widely expressed in cancer cells of the ovary [22], breast [23], bladder [24], lung [25], kidney [26] and other cancers [26]. The special status of KIFC1 in cancer cells is, therefore, well established.…”

“…However, whilst many of the details of exactly how the elevated expression of KIFC1 occurs, remains unclear, part of the story, is beginning to be elucidated. The discovery, in breast cancer tissue, that the amplification of the KIFC1 gene relative to centromeres of chromosome 1 in breast cancer tissue gave the first hint as to why such a high expression of KIFC1 seems to be required in cancer cells [23]. …”

“…However, how those cells with DNA-damage escape from the G2 phase arrest, remains unclear. That lowered missegregation levels of cancer cells actually increases overall genetic instability of the cancer cell group has been verified in ovarian cancer [22], and breast cancer [23]. It has been reasoned that KIFC1 might actually drive malignancy in cancers instead of just acting as a “beacon” for it [48].…”