Hypoxia Drives Centrosome Amplification in Cancer Cells via HIF1 alpha-Dependent Induction of Polo-Like Kinase 4

Centrosome amplification (CA) has been implicated in the progression of various cancer types. Although studies have shown that overexpression of PLK4 promotes CA, the effect of tumor microenvironment on polo-like kinase 4 (PLK4) regulation is understudied. The aim of this study was to examine the role of hypoxia in promoting CA via PLK4. We found that hypoxia induced CA via hypoxia-inducible factor-1 alpha (HIF1 alpha). We quantified the prevalence of CA in tumor cell lines and tissue sections from breast cancer, pancreatic ductal adenocarcinoma (PDAC), colorectal cancer, and prostate cancer and found that CA was prevalent in cells with increased HIF1 alpha levels under normoxic conditions. HIF1 alpha levels were correlated with the extent of CA and PLK4 expression in clinical samples. We analyzed the correlation between PLK4 and HIF1A mRNA levels in The Cancer Genome Atlas (TCGA) datasets to evaluate the role of PLK4 and HIF1 alpha in breast cancer and PDAC prognosis. High HIF1A and PLK4 levels in patients with breast cancer and PDAC were associated with poor overall survival. We confirmed PLK4 as a transcriptional target of HIF1 alpha and demonstrated that in PLK4 knockdown cells, hypoxia-mimicking agents did not affect CA and expression of CA-associated proteins, underscoring the necessity of PLK4 in HIF1 alpha-related CA. To further dissect the HIF1 alpha- PLK4 interplay, we used HIF1 alpha- deficient cells overexpressing PLK4 and showed a significant increase in CA compared with HIF1 alpha-deficient cells harboring wild-type PLK4. These findings suggest that HIF1 alpha induces CA by directly upregulating PLK4 and could help us risk-stratify patients and design new therapies for CA-rich cancers.