Role of KDM2B Epigenetic Factor in Regulating Calcium Signaling in Prostate Cancer Cells

Overview

Journal Saudi Pharm J

Specialty Pharmacy

Date 2024 May 31

PMID 38817821

Authors

Evangelia Pantazaka

Saad Alkahtani

Saud Alarifi

Abdullah A Alkahtane

Christos Stournaras

Galatea Kallergi

Affiliations

Soon will be listed here.

Abstract

KDM2B, a histone lysine demethylase, is expressed in a plethora of cancers. Earlier studies from our group, have showcased that overexpression of KDM2B in the human prostate cancer cell line DU-145 is associated with cell adhesion, actin reorganization, and improved cancer cell migration. In addition, we have previously examined changes of cytosolic Ca, regulated by the pore-forming proteins ORAI and the Ca sensing stromal interaction molecules (STIM), via store-operated Ca entry (SOCE) in wild-type DU-145. This study sought to evaluate the impact of KDM2B overexpression on the expression of key molecules (, , ) and SOCE. Furthermore, this is the first study to evaluate KDM2B expression in circulating tumor cells (CTCs) from patients with prostate cancer. mRNA levels for , , were quantified by RT-PCR. Calcium signals were measured in KDM2B-overexpressing DU-145 cells, loaded with Fura-2. Blood samples from 22 prostate cancer cases were scrutinized for KDM2B expression using immunofluorescence staining and the VyCAP system. KDM2B overexpression in DU-145 cells increased , and mRNA levels and significantly decreased Ca release. KDM2B expression was examined in 22 prostate cancer patients. CTCs were identified in 45 % of these patients. 80 % of the cytokeratin (CK)-positive patients and 63 % of the total examined CTCs exhibited the (CK + KDM2B + CD45-) phenotype. To conclude, this study is the first to report increased expression of KDM2B in CTCs from patients with prostate cancer, bridging and preclinical assessments on the potentially crucial role of KDM2B on migration, invasiveness, and ultimately metastasis in prostate cancer.

References

Yan M, Yang X, Wang H, Shao Q . The critical role of histone lysine demethylase KDM2B in cancer. Am J Transl Res. 2018; 10(8):2222-2233. PMC: 6129528. View

Pantazaka E, Vardas V, Roumeliotou A, Kakavogiannis S, Kallergi G . Clinical Relevance of Mesenchymal- and Stem-Associated Phenotypes in Circulating Tumor Cells Isolated from Lung Cancer Patients. Cancers (Basel). 2021; 13(9). PMC: 8124761. DOI: 10.3390/cancers13092158. View

Liu W, Wang X, Wang Y, Dai Y, Xie Y, Ping Y . SGK1 inhibition-induced autophagy impairs prostate cancer metastasis by reversing EMT. J Exp Clin Cancer Res. 2018; 37(1):73. PMC: 5879613. DOI: 10.1186/s13046-018-0743-1. View

Zhou Y, Gu P, Li J, Li F, Zhu J, Gao P . Suppression of STIM1 inhibits the migration and invasion of human prostate cancer cells and is associated with PI3K/Akt signaling inactivation. Oncol Rep. 2017; 38(5):2629-2636. PMC: 5780014. DOI: 10.3892/or.2017.5961. View

De Nicola I, Guerrieri A, Penzo M, Ceccarelli C, De Leo A, Trere D . Combined expression levels of KDM2A and KDM2B correlate with nucleolar size and prognosis in primary breast carcinomas. Histol Histopathol. 2020; 35(10):1181-1187. DOI: 10.14670/HH-18-248. View

Collins H, Zhang D, Chatham J . STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases. Front Aging. 2022; 3:876785. PMC: 9261457. DOI: 10.3389/fragi.2022.876785. View

Meng S, Tripathy D, Frenkel E, Shete S, Naftalis E, Huth J . Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res. 2004; 10(24):8152-62. DOI: 10.1158/1078-0432.CCR-04-1110. View

Kale R, Samant C, Bokare A, Verma M, Nandakumar K, Bhonde M . Inhibition of SGK1 potentiates the anticancer activity of PI3K inhibitor in NSCLC cells through modulation of mTORC1, p‑ERK and β‑catenin signaling. Biomed Rep. 2023; 19(6):94. PMC: 10603377. DOI: 10.3892/br.2023.1676. View

Koinis F, Zafeiriou Z, Messaritakis I, Katsaounis P, Koumarianou A, Kontopodis E . Prognostic Role of Circulating Tumor Cells in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Cabazitaxel: A Prospective Biomarker Study. Cancers (Basel). 2023; 15(18). PMC: 10527446. DOI: 10.3390/cancers15184511. View

10.

Lang F, Stournaras C, Zacharopoulou N, Voelkl J, Alesutan I . Serum- and glucocorticoid-inducible kinase 1 and the response to cell stress. Cell Stress. 2019; 3(1):1-8. PMC: 6551677. DOI: 10.15698/cst2019.01.170. View

11.

Kappel S, Marques I, Zoni E, Stoklosa P, Peinelt C, Mercader N . Store-Operated Ca Entry as a Prostate Cancer Biomarker - a Riddle with Perspectives. Curr Mol Biol Rep. 2018; 3(4):208-217. PMC: 6010502. DOI: 10.1007/s40610-017-0072-8. View

12.

Kallergi G, Agelaki S, Kalykaki A, Stournaras C, Mavroudis D, Georgoulias V . Phosphorylated EGFR and PI3K/Akt signaling kinases are expressed in circulating tumor cells of breast cancer patients. Breast Cancer Res. 2008; 10(5):R80. PMC: 2614515. DOI: 10.1186/bcr2149. View

13.

Kallergi G, Papadaki M, Politaki E, Mavroudis D, Georgoulias V, Agelaki S . Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients. Breast Cancer Res. 2011; 13(3):R59. PMC: 3218948. DOI: 10.1186/bcr2896. View

14.

Zacharopoulou N, Kallergi G, Alkahtani S, Tsapara A, Alarifi S, Schmid E . The histone demethylase KDM2B activates FAK and PI3K that control tumor cell motility. Cancer Biol Ther. 2020; 21(6):533-540. PMC: 7515453. DOI: 10.1080/15384047.2020.1736481. View

15.

Pantel K, Alix-Panabieres C . Crucial roles of circulating tumor cells in the metastatic cascade and tumor immune escape: biology and clinical translation. J Immunother Cancer. 2022; 10(12). PMC: 9756199. DOI: 10.1136/jitc-2022-005615. View

16.

Stagno M, Zacharopoulou N, Bochem J, Tsapara A, Pelzl L, Al-Maghout T . Istaroxime Inhibits Motility and Down-Regulates Orai1 Expression, SOCE and FAK Phosphorylation in Prostate Cancer Cells. Cell Physiol Biochem. 2017; 42(4):1366-1376. DOI: 10.1159/000479200. View

17.

Sukkar B, Hauser S, Pelzl L, Hosseinzadeh Z, Sahu I, Al-Maghout T . Inhibition of Lithium Sensitive Orai1/ STIM1 Expression and Store Operated Ca2+ Entry in Chorea-Acanthocytosis Neurons by NF-κB Inhibitor Wogonin. Cell Physiol Biochem. 2018; 51(1):278-289. DOI: 10.1159/000495229. View

18.

Liu W, Wang X, Liu Z, Wang Y, Yin B, Yu P . SGK1 inhibition induces autophagy-dependent apoptosis via the mTOR-Foxo3a pathway. Br J Cancer. 2017; 117(8):1139-1153. PMC: 5674106. DOI: 10.1038/bjc.2017.293. View

19.

Hosseinzadeh Z, Hauser S, Singh Y, Pelzl L, Schuster S, Sharma Y . Decreased Na/K ATPase Expression and Depolarized Cell Membrane in Neurons Differentiated from Chorea-Acanthocytosis Patients. Sci Rep. 2020; 10(1):8391. PMC: 7242441. DOI: 10.1038/s41598-020-64845-0. View

20.

Tiffner A, Derler I . Isoform-Specific Properties of Orai Homologues in Activation, Downstream Signaling, Physiology and Pathophysiology. Int J Mol Sci. 2021; 22(15). PMC: 8347056. DOI: 10.3390/ijms22158020. View