HJURP Promotes Malignant Progression and Mediates Sensitivity to Cisplatin and WEE1-inhibitor in Serous Ovarian Cancer

Abstract

Ovarian cancer is the most lethal gynecological malignancy. Recurrence and chemoresistance are tough challenges leading to poor prognosis. HJURP is a molecular chaperone of CENP-A, which is associated with aggressive progression in multiple tumors. However, the function of HJURP in ovarian cancer has not been elucidated. In our study, we found HJURP was over-expressed in ovarian cancer and high expression of HJURP was correlated to unfavorable prognosis. HJURP knockdown could inhibit proliferation, metastasis and induce G0/G1 stagnation of ovarian cancer cells. Besides, next-generation sequencing (NGS) unveiled that WEE1 was down-regulated by silencing HJURP. Further mechanistic research revealed that HJURP regulated WEE1 through MYC, and luciferase assay indicated that MYC was a transcription factor of WEE1. Additionally, we investigated that silencing HJURP increased sensitivity of ovarian cancer cells to cisplatin via MYC/WEE1 axis, and HJURP participated in DNA repair of cisplatin-induced damage. More interestingly, silencing HJURP could enhance sensitivity of ovarian cancer cells to AZD1775 and improve the synergistic effect of cisplatin plus AZD1775 combined therapy. Collectively, our data displays that HJURP promotes tumor progression and chemoresistance of ovarian cancer, and HJURP has potential to be a novel therapeutic target in the combined treatment with cisplatin and AZD1775 in ovarian cancer.

Advances in holliday junction recognition protein (HJURP): Structure, molecular functions, and roles in cancer

“…A recent study revealed that mRNA and protein levels of HJURP in Ovarian serous cystadenocarcinoma (OV) tissues were significantly higher than those detected in normal fallopian tube; consistently, HJURP was also overexpressed in OV cell lines compared to normal ovarian epithelial cells ( Dou et al, 2022 ). High expression of HJURP was shown to be a negative risk factor for PFS by univariate and multifactorial Cox regression analyses, whereas Kaplan-Meier analysis indicated an association between high HJURP expression and worse prognosis, evaluated by both OS and PFS, in OV patients ( Dou et al, 2022 ). This is consistent with the previous findings by Li et al, who showed that increased expression of HJURP is an independent negative prognostic biomarker in patients with advanced serous OV ( Li et al, 2018 ) ( Table 1 ).…”

“…Silencing of HJURP significantly inhibited OV cell proliferation by inducing G0/G1 arrest and decreased also the migration and invasion potential of these cells. Of note, although HJURP silencing in OV cells did not promote apoptosis, this process was enhanced when combined with cisplatin treatment ( Dou et al, 2022 ). Interestingly, a positive association between HJURP expression and EMT was established by assays that showed that both vimentin and Slug expression was downregulated after HJURP knockdown, whereas Slug expression was significantly upregulated upon HJURP overexpression in SKOV3 cells ( Dou et al, 2022 ).…”

“…Aberrant HJURP expression is common in tumors, including hepatocellular carcinoma ( Chen T. et al, 2019 ), renal cell carcinoma ( Zhang et al, 2021 ), ovarian cancer ( Dou et al, 2022 ), osteosarcoma ( Jia et al, 2022 ), pancreatic cancer ( Wang C. J. et al, 2020 ), and oral cancer ( Tsevegjav et al, 2022 ). Abnormal activation of HJURP may be linked to unrestricted proliferation of tumor cells ( Kato et al, 2007 ), an effect associated with enhanced chromosomal stability and promotion of DNA DSB repair via the homologous recombination pathway ( Mishra et al, 2011 ; Vishwakarma and McManus, 2020 ).…”

TMED9Expression Level as a Biomarker of Epithelial Ovarian Cancer Progression and Prognosis

“…Public database. To validate our RNA-seq data, three datasets [GSE190688 (21), GSE54388 (22), GSE 40595 (23)] that analyzed DEGs between normal and high-grade serous ovarian cancer (HGSOC) samples were downloaded from the GEO Database (https://www.ncbinlm.nih.gov/geo/, accessed on December 20, 2021). An online public database, Kaplan-Meier Plotter (http://www.kmplot.com) which contains 10,293 lung, breast, gastric, and ovarian cancer samples to evaluate clinical outcomes of 54,675 genes were used to verify the prognostic significance of TMED9.…”

Histone Chaperones and Digestive Cancer: A Review of the Literature

“…An inhibitor of HJURP has not yet been reported. HJURP has been demonstrated to play a significant role in numerous tumors, including prostate [ 108 ], breast [ 109 ], and ovarian cancers [ 110 ]. Therefore, it is essential to further investigate the function and mechanism of HJURP in tumors of the digestive tract.…”