Hypoxia Drives Centrosome Amplification in Cancer Cells via HIF1a-Dependent Induction of Polo-Like Kinase 4

Abstract

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 promotingCAvia PLK4.Wefound that hypoxia induced CA via hypoxia-inducible factor-1a (HIF1a). 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 HIF1a levels under normoxic conditions. HIF1a levels were correlated with the extent of CA and PLK4 expression in clinical samples. We analyzed the correlation between PLK4 and HIF1AmRNAlevels in The Cancer Genome Atlas (TCGA) datasets to evaluate the role of PLK4 and HIF1a 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 HIF1a 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 HIF1a-related CA. To further dissect the HIF1a-PLK4 interplay, we used HIF1a-deficient cells overexpressing PLK4 and showed a significant increase in CA compared with HIF1a-deficient cells harboring wild-type PLK4. These findings suggest that HIF1a induces CA by directly upregulating PLK4 and could help us risk-stratify patients and design new therapies for CA-rich cancers.