title: Epigenetic silencing of CXCR4 promotes loss of cell adhesion in cervical cancer.
abstract: In the network of chemokine signaling pathways, recent reports have described the SDF-1α/CXCR4 axis and its role in cancer progression and metastasis. Interestingly, we found downregulation of CXCR4 at both transcript and protein level in cervical cancer cell lines and primary tumors. We also found CXCR4 promoter hypermethylation in cervical cancer cell lines and primary biopsy samples. DNA hypomethylating drug 5-AZA-2'-deoxycytidine and histone deacetylase inhibitor Trichostatin A treatments in cell lines reactivate both CXCR4 transcription and protein expression. Cell adhesion assay demonstrated that autocrine SDF-1α promotes the loss of cell adhesion while paracrine SDF-1α predominantly protects the normal cervical cells from loss of cell adhesion. Cervical cancer cell line C-33A having increased expression of CXCR4 after TSA treatment showed increased cell adhesion by paracrine source of SDF-1α in comparison to untreated C-33A. These findings demonstrate the first evidence that epigenetic silencing of CXCR4 makes the cells inefficient to respond to the paracrine source of SDF-1α leading to loss of cell adhesion, one of the key events in metastases and progression of the disease. Our results provide novel insight of SDF-1α/CXCR4 signaling in tumor microenvironment which may be promising to further delineate molecular mechanism of cervical carcinogenesis.
authors.affiliation: Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi 221005, India.
authors.forename: Suresh Singh
authors.identifier: 0000-0003-0309-8747
authors.initials: SS
authors.lastname: Yadav
authors.affiliation: Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi 221005, India.
authors.forename: Shyam Babu
authors.initials: SB
authors.lastname: Prasad
authors.affiliation: Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi 221005, India.
authors.forename: Mitali
authors.initials: M
authors.lastname: Das
authors.affiliation: Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi 221005, India.
authors.forename: Soni
authors.initials: S
authors.lastname: Kumari
authors.affiliation: Department of Obstetrics and Gynecology, Banaras Hindu University, Varanasi 221005, India.
authors.forename: Lakshmi Kant
authors.initials: LK
authors.lastname: Pandey
authors.affiliation: Department of Zoology, Mahila Mahavidyalaya, Banaras Hindu University, Varanasi 221005, India.
authors.forename: Sunita
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Radiotherapy & Radiation Medicine, Banaras Hindu University, Varanasi 221005, India.
authors.forename: Satyajit
authors.initials: S
authors.lastname: Pradhan
authors.affiliation: Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi 221005, India.
authors.forename: Gopeshwar
authors.identifier: 0000-0001-5851-9997
authors.initials: G
authors.lastname: Narayan
mesh_terms: D000328:Adult; D000368:Aged; D002448:Cell Adhesion / Q000235:genetics*; D045744:Cell Line, Tumor; D002584:Cervix Uteri / Q000737:chemistry / Q000473:pathology; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D008875:Middle Aged; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D059016:Tumor Microenvironment; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4