Daxx is one of the few “constitutive” components of PML-NBs, and is a multifunctional protein that regulates a wide range of cellular signaling pathways for both cell survival and apoptosis. It is a critical regulator of T-lymphocyte homeostasis by decreasing TCR-induced cell proliferation and by promoting Fas-mediated cell death . Daxx has been shown that it acts as a scaffold that stimulates the phosphorylation of p53 by the protein kinase Hipk2 . As a novel APC/C inhibitor frequently overexpressed in prostate cancer, Daxx was frequently upregulated in prostate cancer tissues, and its expression level positively correlated with the Gleason score and disease metastasis. Furthermore, its ectopic expression in a non-malignant prostate epithelial cell line induced polyploidy under mitotic stress. Daxx may promote chromosome instability during prostate cancer development . So it implies Daxx might play a critical role in the cellular transformation and cancer development.
Daxx’s location within PML-NBs is crucial for normal cellular shapes and functions. Under some influencing factors, the subcellular localization of Daxx can be changed by modification or interacting with other proteins. The changing of Daxx location can affect the cell cycle, the antiviral, pro-apoptotic or antiapoptotic activities and play a role in the transcriptional regulation . In recently study on brain tissue infected by reoviridae, it was found that the up-regulation of Daxx through IFN-I mechanism might depend on the Daxx positioning cytoplasm or nucleus to play a role in cell apoptosis  which showed that Daxx orientation was related to the apoptosis role of host cell after viral infections. In Human cytomegalovirus (HCMV)-infected cells, Daxx was bound to HCMV virion tegument protein pp71, which also promoted its sumoylation . If HCMV didn’t express the protein IE1, coat protein pp71 in cytoplasm didn’t combine with Daxx, therefore Daxx would silence the viral genes and inhibit the viral replication. But the newly synthesized pp71 protein could enter into the nucleus to interact with Daxx and reverse inhibition mediated by Daxx, which was advantageous to the viral genes expression . But later it was found that HCMV infected cells could close the mRNA expression of viral early protein gene IE1 and IE2 at S/G2 phase, which didn’t rely on the functions of Daxx and PML. So, the nuclear, genome-wide repression of HCMV was typically mediated by the intrinsic immune defence at ND10 structures . Adenovirus(Ad) E1B-55kd protein can also interact with Daxx and break the colocalization of Daxx and PML within PML-NBs , so affect the transcription inhibitory activities of Daxx and its other functions . It was shown that the protein expression of chromatin remodeler Daxx in high grade invasive urothelial carcinoma of the bladder and in its preinvasive phases changed through quantitative immunohistochemical analysis . Which effects have Daxx in the progress of cervical cancer induced by HR-HPVs?
Like adenovirus, HPVs replicate in the nucleus. We speculate that after HPVs infections in cervical epithelial tissue, the normal shape of PML (NBs) might be changed and following the location changing of Daxx, furthermore it would affect the cellular resistance for the HPVs. Owing to the HPVs persisted infections in cervical epithelial tissues, cervical cancer would happen eventually. In this study we found all Daxx existed in nuclei of the normal cervical epithelial cells. however, in HR-HPV positive cells of CIN, majority of Daxx already transfered from the nuclei and gathered near the nuclear membrane, but a little existed in nuclei, which was further confirmed by the consistance of its loation in Caski cells with HPV16 positive. With the hyperplasia and deterioration of epithelial tissue, Daxx translocated through nuclear membrane into the cytoplasm, and intensive distribution in the cell membrane. This study also confirmed that the translocated process is completed in CIN, due to Daxx distribution and localization in CIN were all identity with that in CIN, carcinoma in situ and invading cervical cancer tissues. Our study results suggested that Daxx might play an important role in the antineoplastic early stage. While the host cells had been immortalized, Daxx would play a little role in antitumor.
Owing to the obvious location changing of Daxx between in CINI and CINII, it may be an important target protein for protecting cervical tissue against HPVs infections inducing cervical cancer. In the cervical epithelial cells persistently infected by HPVs, if Daxx translocating from the nucleus to the cytoplasm can be intervened, it would be possible to avoid cells immortalization, and prevent the cervical cancer induced by HR-HPVs.