Hypoxia Drives Centrosome Amplification in Cancer Cells via HIF1α-dependent Induction of Polo-Like Kinase 4

Mittal, Karuna; Kaur, Jaspreet; Sharma, Shaligram; Sharma, Nivya; Wei, Guanhao; Choudhary, Ishita; Imhansi-Jacob, Precious; Maganti, Nagini; Pawar, Shrikant; Rida, Padmashree C.G.; Toss, Michael S.; Aleskandarany, Mohammed A.; Janssen, Emiel A. M.; Søiland, Håvard; Gupta, Meenakshi V.; Reid, Michelle D.; Rakha, Emad A.; Aneja, Ritu

doi:10.1158/1541-7786.mcr-20-0798

Cited by 13 publications

(14 citation statements)

References 57 publications

(77 reference statements)

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“…22 Another clue of PLK4 involvement in PCa comes from a recently published study where hypoxia-inducible factor-1α (HIF1α) has been demonstrated to induce CA by upregulating PLK4 in multiple cancers including PCa. 23 Herein, we evaluated the cause of CA in PCa, determined the role of PLK4 in CA in PCa, analyzed the prognostic value of PLK4 expression in PCa, and explored the potential of PLK4 inhibition as a strategy to treat PCa.…”

Section: Introductionmentioning

confidence: 99%

“…One clue of the involvement of PLK4 in PCa comes from the finding that CAND1 is upregulated in PCa and promotes CA by enhancing PLK4 stability 22 . Another clue of PLK4 involvement in PCa comes from a recently published study where hypoxia‐inducible factor‐1α (HIF1α) has been demonstrated to induce CA by upregulating PLK4 in multiple cancers including PCa 23 …”

Section: Introductionmentioning

confidence: 99%

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PLK4 is upregulated in prostate cancer and its inhibition reduces centrosome amplification and causes senescence

et al. 2022

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Background Identification of novel molecular target(s) is important for designing newer mechanistically driven approaches for the treatment of prostate cancer (PCa), which is one of the main causes of morbidity and mortality in men. In this study, we determined the role of polo‐like kinase 4 (PLK4), which regulates centriole duplication and centrosome amplification (CA), in PCa. Materials and Methods Employing human PCa tissue microarrays, we assessed the prevalence of CA, correlated with Gleason score, and estimated major causes of CA in PCa (cell doubling vs. centriole overduplication) by staining for mother/mature centrioles. We also assessed PLK4 expression and correlated it with CA in human PCa tissues and cell lines. Further, we determined the effects of PLK4 inhibition in human PCa cells. Results Compared to benign prostate, human PCa demonstrated significantly higher CA, which was also positively correlated with the Gleason score. Further, most cases of CA were found to arise by centriole overduplication rather than cell doubling events (e.g., cytokinesis failure) in PCa. In addition, PLK4 was overexpressed in human PCa cell lines and tumors. Moreover, PLK4 inhibitors CFI‐400945 and centrinone‐B inhibited cell growth, viability, and colony formation of both androgen‐responsive and androgen‐independent PCa cell lines. PLK4 inhibition also induced cell cycle arrest and senescence in human PCa cells. Conclusions CA is prevalent in PCa and arises predominantly by centriole overduplication as opposed to cell doubling events. Loss of centrioles is cellular stress that can promote senescence and suggests that PLK4 inhibition may be a viable therapeutic strategy in PCa.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PLK4 is upregulated in prostate cancer and its inhibition reduces centrosome amplification and causes senescence

et al. 2022

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“…A recent study showed that hypoxia can promote CA via HIF1α-dependent induction of PLK4 38 . Out of the 73 cell lines screened, 25 were derived and maintained in low oxygen growth conditions (5% O2; termed here as low-O2 cell lines).…”

Section: Resultsmentioning

confidence: 99%

Molecular landscape and functional characterization of centrosome amplification in ovarian cancer

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et al. 2022

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High grade serous ovarian carcinoma (HGSOC) is the major cause of gynaecological cancer-related deaths in the Western world, and is characterised by extreme chromosomal instability (CIN). CIN is a key mediator of clonal diversity and treatment resistance and is associated with poor disease outcome. An increased understanding of underlying mechanisms driving CIN in HGSOC is therefore critical to predict outcomes and identify novel therapeutic approaches. The centrosome is the main microtubule organising centre of a cell and plays a crucial role during cell division and chromosome segregation. Missegregation of chromosomes at high rates results in CIN; and supernumerary centrosomes have previously been associated with aneuploidy and poor disease outcome in several cancers. However, relatively little is currently known about centrosome abnormalities and associated molecular features in HGSOC. Here, we developed high-throughput microscopy approaches to provide the first large-scale characterisation of centrosome amplification (CA) in >300 clinical tissue samples and >70 ovarian cancer cell lines. We report that HGSOC frequently shows supernumerary centrosomes with marked intra-tissue heterogeneity. Imaging and shallow whole genome sequencing experiments further revealed that CA in HGSOC is associated with the presence of micronuclei, increased genomic abnormality and, interestingly, genomic subclonality, highlighting CA as a potential driver of tumour evolution. Further, using RNA sequencing, and drug assays on selected cell lines we found that cells with high CA show upregulated NFκB signalling and increased resistance to standard-of-care paclitaxel as well as other therapeutic agents. In addition, our detailed phenotypic, genomic, and transcriptomic characterisation of >70 ovarian cancer cell lines will provide an important platform for future studies on CIN and CA in ovarian cancer.

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“…The present study indicated that both PLK4 protein and mRNA expression were upregulated in tumor tissues compared with in adjacent tissues of patients with RCC. The possible explanations are as follows: i) PLK4 expression was positively associated with the number of centrioles that were excessively amplified in cancer cells, and thus, its expression levels were upregulated in tumor tissues compared with in adjacent tissues of patients with RCC (26). ii) Although PLK4 could autoregulate its stability to prevent centrosome amplification, under the cancerous condition, it has been observed that some specific genes, such ------------------------------------------------------ as centrosomal protein 131, could regulate PLK4 stability and further promote centrosome amplification (27,28).…”

Section: Discussionmentioning

confidence: 99%

Aberrant expression of polo‑like kinase 4 in renal cell carcinoma: Association with clinicopathological characteristics and long‑term survival

et al. 2022

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Polo-like kinase 4 (PLK4) promotes tumorigenesis and is associated with the prognosis of several solid tumors, while its clinical role in patients with renal cell carcinoma (RCC) remains unidentified. The present study aimed to analyze the association of PLK4 with clinicopathological characteristics and long-term prognosis in patients with RCC. The present study detected PLK4 protein and mRNA expression using immunohistochemical and reverse transcription-quantitative PCR assays in 120 patients with RCC. Disease-free survival (DFS) and overall survival (OS) time were calculated based on a median follow-up duration of 6.9 years (range, 1.2-9.9 years). PLK4 protein expression was elevated in tumor tissues compared with adjacent tissues (P<0.001). Upregulation of PLK4 protein was associated with increased T stage (P=0.023), N stage (P=0.014) and TNM stage (P=0.007). Additionally, elevated tumor PLK4 protein expression exhibited an associating trend (without statistical significance) with reduced DFS rate (P=0.066) and was associated with decreased OS rate (P=0.036). However, univariate Cox's regression analysis indicated that high PLK4 protein expression (compared with low PLK4 protein expression) was associated with reduced OS rate (P=0.040) but not with PFS rate (P=0.070). Following adjustment by multivariate Cox's regression analysis, PLK4 protein expression was associated with neither DFS nor OS rate (both P>0.050). Additionally, PLK4 mRNA expression was further detected in some patients (for which fresh specimens frozen in liquid nitrogen were available) to validate the aforementioned observations, and the expression was elevated in tumor tissues compared with adjacent tissues. Furthermore, increased PLK4 mRNA expression was associated with tumor size ≥7 cm, high TNM stage and reduced DFS rate (all P<0.050). PLK4 possesses a certain clinical utility in monitoring the clinical stage of patients with RCC, while its prognostic value requires further validation.

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Hypoxia Drives Centrosome Amplification in Cancer Cells via HIF1α-dependent Induction of Polo-Like Kinase 4

Cited by 13 publications

References 57 publications

PLK4 is upregulated in prostate cancer and its inhibition reduces centrosome amplification and causes senescence

PLK4 is upregulated in prostate cancer and its inhibition reduces centrosome amplification and causes senescence

Molecular landscape and functional characterization of centrosome amplification in ovarian cancer

Aberrant expression of polo‑like kinase 4 in renal cell carcinoma: Association with clinicopathological characteristics and long‑term survival

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