HPV E6 and E7 oncoproteins cooperatively alter the expression of Disc Large 1 polarity protein in epithelial cells

DIZANZO, MARÍA PAULA; MARZIALI, FEDERICO; BRUNET AVALOS, CLARISSE; BUGNON VALDANO, MARINA; LEIVA, SANTIAGO; CAVATORTA, ANA LAURA; GARDIOL, DANIELA

BMC CANCER

BIOMED CENTRAL LTD

Año: 2020 vol. 20

1471-2407

Background: Persistent infection with high-risk Human Papillomavirus (HPVs) is associated with the developmentof cervical cancer. The transforming capacity of these viruses relies on the cooperative action of the E6 and E7 viraloncoproteins. Among the oncogenic activities of E6, the interaction and interference with cell polarity PDZ proteinshave been well established. One of the most characterized PDZ targets of HPV E6 is human Disc large 1 (DLG1), ascaffolding protein involved in the control of cell polarity and proliferation. Interestingly, in cervical squamousintraepithelial lesions, alterations in DLG1 expression were observed in association to tumour progression. Moreover,the expression of both HPV E6 and E7 proteins may be responsible for the changes in DLG1 abundance and celllocalization observed in the HPV-associated lesions.Methods: Due to the relevance of DLG1 deregulation in tumour development, we have performed an in-depthinvestigation of the expression of DLG1 in the presence of the HPV oncoproteins in epithelial cultured cells. Theeffects of HPV E6 and E7 proteins on DLG1 abundance and subcellular localization were assessed by western blotand confocal fluorescence microscopy, respectively.Results: We demonstrated that the relative abundance of HPV-18 E6 and DLG1 is a key factor that contributes todefining the expression abundance of both proteins. We also show here that a high expression level of DLG1 maynegatively affect HPV-18 E6 nuclear expression. Moreover, the co-expression of HPV-18 E6 and E7 produces astriking effect on DLG1 subcellular localization and a co-distribution in the cytoplasmic region. Interestingly, HPV-18E7 is also able to increase DLG1 levels, likely by rescuing it from the E6-mediated proteasomal degradation.Conclusions: In general, the data suggest that HPV-18 E6 and E7 may have opposing activities in regards to theregulation of DLG1 levels and may cooperatively contribute to its subcellular redistribution in the HPV context.These findings constitute a step forward in understanding the differential expression of DLG1 during tumourprogression in an HPV-associated model.