The CREB1/WNK1 axis promotes the tumorigenesis of ovarian cancer via regulating HIF-1

Yifei Ma; Hui Zong; Pan Pan; Hui Shang; Xingsheng Yang

doi:10.1016/j.yexcr.2024.114006

The CREB1/WNK1 axis promotes the tumorigenesis of ovarian cancer via regulating HIF-1

Exp Cell Res. 2024 Apr 8;438(1):114006. doi: 10.1016/j.yexcr.2024.114006. Online ahead of print.

Authors

Yifei Ma¹, Hui Zong², Pan Pan³, Hui Shang⁴, Xingsheng Yang⁵

Affiliations

¹ Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, PR China; Department of Obstetrics and Gynecology, Jinan Central Hospital, Jinan, 250013, Shandong, PR China.
² Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, PR China.
³ Department of Pathology, Jinan Central Hospital, Jinan, 250013, Shandong, PR China.
⁴ Department of Obstetrics and Gynecology, Jinan Central Hospital, Jinan, 250013, Shandong, PR China.
⁵ Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, PR China. Electronic address: xingshengyang@sdu.edu.cn.

PMID: 38599542
DOI: 10.1016/j.yexcr.2024.114006

Abstract

The aim of this study was to explore the functions and molecular mechanisms of the WNK lysine deficient protein kinase 1 (WNK1) in the development of ovarian cancer. Firstly, loss- and gain-of-function assays were carried out and subsequently cell proliferation, apoptosis, invasion and migration were detected. Furthermore, WNK1 action on glucose uptake, lactate production and adenosine triphosphate (ATP) level were assessed. The roles of WNK1 on cisplatin resistance were explored using CCK-8, colony formation, and flow cytometry in vitro. Immunohistochemistry, Western blot and qRT-PCR were conducted to determine the protein and mRNA expression. Additionally, tumor growth in vivo was also monitored. We found that the overexpression of WNK1 predicted a bad prognosis of ovarian cancer patients. WNK1 enhanced the malignant behavior and facilitated glycolysis of ovarian cancer cells. Moreover, WNK1 increased cisplatin resistance in ovarian cancer cells. Mechanistically, we found that WNK1 expression was promoted by CREB1 at the transcriptional level. And CREB1 could facilitate ovarian cancer cells malignant behavior through target upregulating WNK1. Besides, we also showed that WNK1 facilitated the malignant behavior by accelerating HIF-1 expression. In xenograft tumor tissues, the downregulation of WNK1 significantly reduced HIF-1α expression. These data demonstrated that the CREB1/WNK1 axis could promote the tumorigenesis of ovarian cancer via accelerating HIF-1 expression, suggesting that the CREB1/WNK1 axis could be a potential target during the therapy of ovarian cancer.

Keywords: CREB1/WNK1 axis; Cisplatin resistance; Glycolysis; HIF-1; Ovarian cancer.