HPV16-transformed human keratinocytes depend on SIX1 expression for proliferation and HPV E6/E7 gene expression

Hosseinipour, Maria; Wan, Fang; Altomare, Diego; Creek, Kim E.; Pirisi, Lucia

doi:10.1016/j.virol.2019.08.009

Cited by 5 publications

(3 citation statements)

References 38 publications

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“…One of the IFN-dependent TF that can bind several domains of the SARS-CoV-2 genome is SIX1. It plays a critical role in embryogenesis, is not expressed in normal adult tissue, but is expressed in many malignancies, including cervical [39] and HIV-associated lung cancer [40]. However, Hypoxia and HIF-1α can increase SIX1 expression, which reciprocally stimulates HIF-1α expression under both normoxic and hypoxic conditions, thereby creating a positive feedback regulatory loop [41].…”

Section: Discussionmentioning

confidence: 99%

Severe Acute Respiratory Syndrome Coronavirus 2 could exploit human transcription factors involved in Interferon-mediated response

Bari

Franzin

Picerno

et al. 2020

Preprint

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Background The novel SARS-CoV-2 causing the pandemic acute respiratory disease COVID-19 is considered a worldwide emergency since no vaccines or effective antiviral are still available. As virus are dependent on the host transcriptional factors (TFs) to express the viral genes, efforts are required to understand the molecular interplay between virus and host response. Methods By bioinformatic analysis, we investigated human TFs involved in viral transcription. In particular, we analyzed the key role of the TF induced by Interferon regulatory factors (IRFs) exploiting the way of antiviral response related to interferon antiviral cytokines released during an infection. We compared SARS-CoV-2 consensus sequence from Italian patients with sequences in Coronaviridae ViPR database, to identify elements and TF binding sites that were present uniquely in the Italian viral sequence.Results Several TFs were induced by IRFs, others were induced by IFN-stimulated gene factor 3 (ISGF3) and by un-phosphorylated ISGF3 that was found to promote the transcription of several viral open reading frame. These data shed light on SARS-CoV2 dependence from the host transcription machinery associated to interferon-related antiviral response. We found binding sites for 11 TF present only in sequence of virus infecting humans and among these IRF8, IRF4, GLIS2, POU4F2 that were expressed in response to the viral infection and induced by interferon. POU4F2 binds in ORF1ab promoter; IRF8, and IRF4 both bind within the ORF1ab gene.Conclusions Our data suggest that SARS-CoV-2 can exploit the interferon-related host response, inducing the expression of genes by host TF involved in the regulation of transcription by RNA polymerase II, thus facilitating its own replication cycle.These data strengthen our knowledge about the transcription and replicative activity of the virus and could pave the way for new targets drug design.

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Section: Discussionmentioning

confidence: 99%

Severe Acute Respiratory Syndrome Coronavirus 2 could exploit human transcription factors involved in Interferon-mediated response

Bari

Franzin

Picerno

et al. 2020

Preprint

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“…As the cells progress, E7 levels increase and so do SIX1 levels, driving TGF-β signaling to non-canonical pathways, freeing the cells from growth inhibition by TGF-β, promoting differentiation resistance and EMT. When we attempted to reduce SIX1 levels in HKc/ HPV16 and HKc/DR with siRNA approaches, we found that these cells did not tolerate a loss of SIX1 and either overcame the siRNA effects or died (Hosseinipour et al 2019). Fig.…”

Section: Hpv-mediated Carcinogenesis and Tumor Progression In Vivo And In Vitromentioning

confidence: 95%

Human papillomavirus-mediated carcinogenesis and tumor progression

Abboodi

Delva

Emmel

et al. 2021

GENOME INSTAB. DIS.

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High-risk human papillomaviruses (HPV) cause 5% of all human cancers and are primary etiologic agents of cervical, anal, and oropharyngeal cancer. HPV infection is necessary, but not sufficient per se to produce cancer: additional changes must occur that transform HPV-infected cells to malignancy. The HPV oncoproteins E6 and E7 immortalize human keratinocytes, cervical cells, and fibroblasts in culture. Each oncoprotein interacts with a variety of cellular binding partners; most important for transformation are E6 and E7's interactions with p53 and RB (respectively) which lead to degradation of p53 and RB through the ubiquitin pathway. Inactivation of p53 and RB leads to inactivation of pivotal cell cycle checkpoints, thereby stimulating cell proliferation and allowing cell division to occur independently of the presence of DNA damage, replicative stress, and other such insults, leading to genome instability. Continuous expression of E6/E7 drives the proliferation and progression of most HPV-mediated cancers of the cervix and a substantial fraction of those of the oropharynx. However, at both cancer sites, "HPV-inactive" tumors that contain HPV DNA, but do not express E6/E7 arise. We propose that these HPV-inactive cancers begin as HPV-driven lesions, but lose E6/E7 expression at some point during progression. We have recently shown that p53 deletion in HPV-immortalized, premalignant cells allows for the emergence of cell populations that no longer express E6/E7. These findings corroborate the notion of a pivotal role of p53 in the context of HPV-mediated transformation, both at the initiation and progression stages of cancer development.

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“…One mechanism of action by which manzamine-A acts is as a novel small molecule inhibitor targeting cells that express a critical homeobox gene SIX1 [ 45 ]. SIX1 expression has been linked to organogenesis, DNA specificity, protein–protein interactions, and proliferation and survival of cells [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ]. Thus, from a cellular development and maintenance perspective the use of manzamine-A and related alkaloid analogs may be of concern.…”

Section: Introductionmentioning

confidence: 99%

Manzamine-A Alters In Vitro Calvarial Osteoblast Function

et al. 2022

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Manzamine-A is a marine-derived alkaloid which has anti-viral and anti-proliferative properties and is currently being investigated for its efficacy in the treatment of certain viruses (malaria, herpes, HIV-1) and cancers (breast, cervical, colorectal). Manzamine-A has been found to exert effects via modulation of SIX1 gene expression, a gene critical to craniofacial development via the WNT, NOTCH, and PI3K/AKT pathways. To date little work has focused on Manzamine-A and how its use may affect bone. We hypothesize that Manzamine-A, through SIX1, alters bone cell activity. Here, we assessed the effects of Manzamine-A on cells that are responsible for the generation of bone, pre-osteoblasts and osteoblasts. PCR, qrtPCR, MTS cell viability, Caspase 3/7, and functional assays were used to test the effects of Manzamine-A on these cells. Our data suggests Six1 is highly expressed in osteoblasts and their progenitors. Further, osteoblast progenitors and osteoblasts exhibit great sensitivity to Manzamine-A treatment exhibited by a significant decrease in cell viability, increase in cellular apoptosis, and decrease in alkaline phosphatase activity. In silico binding experiment showed that manzamine A potential as an inhibitor of cell proliferation and survival proteins, i.e., Iκb, JAK2, AKT, PKC, FAK, and Bcl-2. Overall, our data suggests Manzamine-A may have great effects on bone health overall and may disrupt skeletal development, homeostasis, and repair.

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HPV16-transformed human keratinocytes depend on SIX1 expression for proliferation and HPV E6/E7 gene expression

Cited by 5 publications

References 38 publications

Severe Acute Respiratory Syndrome Coronavirus 2 could exploit human transcription factors involved in Interferon-mediated response

Severe Acute Respiratory Syndrome Coronavirus 2 could exploit human transcription factors involved in Interferon-mediated response

Human papillomavirus-mediated carcinogenesis and tumor progression

Manzamine-A Alters In Vitro Calvarial Osteoblast Function

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