The human papillomavirus (HPV) family includes more than 170 different types of virus that infect stratified epithelium. High-risk HPV is well established as the primary cause of cervical cancer, but in recent years, a clear role for this virus in other malignancies is also emerging. Indeed, HPV plays a pathogenic role in a subset of head and neck cancers—mostly cancers of the oropharynx—with distinct epidemiological, clinical and molecular characteristics compared with head and neck cancers not caused by HPV. This review summarises our current understanding of HPV in these cancers, specifically detailing HPV infection in head and neck cancers within different racial/ethnic subpopulations, and the differences in various aspects of these diseases between women and men. Finally, we provide an outlook for this disease, in terms of clinical management, and consider the issues of ‘diagnostic biomarkers’ and targeted therapies.

Here we describe the LifeTime Initiative, which aims to track, understand and target human cells during the onset and progression of complex diseases, and to analyse their response to therapy at single-cell resolution. This mission will be implemented through the development, integration and application of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during the progression from health to disease. The analysis of large molecular and clinical datasets will identify molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. The timely detection and interception of disease embedded in an ethical and patient-centred vision will be achieved through interactions across academia, hospitals, patient associations, health data management systems and industry. The application of this strategy to key medical challenges in cancer, neurological and neuropsychiatric disorders, and infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade.

Recent evidence has shown a number of extra-skeletal functions of Vitamin D (VD), primarily involving the immune system. One of these functions is mediated by the modulation of gut microbiota, whose alterations are linked to many diseases. Our purpose is to contribute to the understanding of existing evidence on the association between VD and gastrointestinal microbiota alterations. A systematic review of studies with human subjects has been conducted up to January 2021. We included publications reporting the association between gut microbiota and VD, including VD supplementation, dietary VD intake and/or level of 25(OH)D. We identified 25 studies: 14 were interventional and 11, observational. VD supplementation was found to be associated with a significant change in microbiome composition, in particular of Firmicutes, Actinobacteria and Bacteroidetes phyla. Furthermore, Firmicutes were found to be correlated with serum VD. Concerning alpha and beta diversity, a high nutritional intake of VD seems to induce a shift in bacterial composition and/or affects the species’ richness. Veillonellaceae and Oscillospiraceae families, in the Firmicutes phylum, more frequently decreased with both increasing levels of 25(OH)D and vitamin D supplementation. We found evidence of an association, even though the studies are substantially heterogeneous and have some limitations, resulting sometimes in conflicting results. To further understand the role of VD on the modulation of the gastrointestinal microbiota, future research should be geared toward well-designed animal-based studies or larger randomized controlled trials (RCTs).

Human papilloma viruses (HPVs) are a group of double-stranded DNA viruses known to be the primary cause of cervical cancer. In addition, evidence has now established their role in non-melanoma skin cancers, head and neck cancer (HNC), and the development of other anogenital malignancies. The prevalence of HPV-related HNC, in particular oropharyngeal cancers, is rapidly increasing, foreseeing that HPV-positive oropharyngeal cancers will outnumber uterine cervical cancers in the next 15–20 years. Therefore, despite the successful advent of vaccines originally licensed for cervical cancer prevention, HPV burden is still very high, and a better understanding of HPV biology is urgently needed. Autophagy is the physiological cellular route that accounts for removal, degradation, and recycling of damaged organelles, proteins, and lipids in lysosomal vacuoles. In addition to this scavenger function, autophagy plays a fundamental role during viral infections and cancers and is, therefore, frequently exploited by viruses to their own benefit. Recently, a link between HPV and autophagy has clearly emerged, leading to the conceivable development of novel anti-viral strategies aimed at restraining HPV infectivity. Here, recent findings on how oncogenic HPV16 usurp autophagy are described, highlighting similarities and differences with mechanisms adopted by other oncoviruses.

UBC9, the sole E2-conjugating enzyme required for SUMOylation, is a key regulator of essential cellular functions and, as such, is frequently altered in cancers. Along these lines, we recently reported that its expression gradually increases during early stages of human papillomavirus (HPV)-mediated cervical lesions transformation. However, a better understanding of how UBC9 is exploited by transforming viral oncoproteins is still needed. In the present study, we show that in human samples HPV drives UBC9 up-regulation also in very early steps of head and neck tumorigenesis, pointing to the important role for UBC9 in the HPV-mediated carcinogenic program. Moreover, using HPV-infected pre-cancerous tissues and primary human keratinocytes as the natural host of the virus, we investigate the pathological meaning and the cellular mechanisms responsible for UBC9 de-regulation in an oncoviral context. Our results show that UBC9 overexpression is promoted by transforming viral proteins to increase host cells’ resistance to apoptosis. In addition, ultrastuctural, pharmacological and genetic approaches crucially unveil that UBC9 is physiologically targeted by autophagy in human cells. However, the presence of HPV E6/E7 oncoproteins negatively impacts the autophagic process through selective inhibition of autophagosome-lysosome fusion, finally leading to p53 dependent UBC9 accumulation during viral-induced cellular transformation. Therefore, our study elucidates how UBC9 is manipulated by HPV oncoproteins, details the physiological mechanism by which UBC9 is degraded in cells, and identifies how HPV E6/E7 impact on autophagy. These findings point to UBC9 and autophagy as novel hallmarks of HPV oncogenesis, and open innovative avenues towards the treatment of HPV-related malignancies. High risk HPV is the primary cause of cervical cancer and in recent years a clear role for the virus in other anogenital malignancies, in head and neck and in nonmelanoma skin cancers is emerging. Cellular transformation is mediated by the viral oncoproteins E6 and E7 that have the ability to target several pathways. We recently demonstrated that UBC9, the key enzyme of the Small Ubiquitin-like Modifier (SUMO) pathway, is up-regulated during pre-cancerous and cancerous stages of cervical carcinogenesis. In this study, we elucidate the pathological impact and the cellular mechanisms responsible for UBC9 accumulation promoted by HPV in cervical and head and neck pre-cancerous tissues. Indeed, we show that UBC9 is physiologically degraded in cells by autophagy, and that the expression of HPV oncoproteins impairs autophagy finally leading to UBC9 accumulation and apoptosis resistance of infected cells. Our results therefore identify UBC9 and autophagy as important co-factors to prime early stages of HPV-mediated tumorigenesis, and pinpoint novel therapeutic strategies for treatment of carcinogenic HPV infections.

Histone deacetylase 1 (HDAC1) is an essential epigenetic regulator belonging to a highly conserved family of deacetylases. Increased HDAC1 activity and expression often correlates with neoplastic transformation. Here we show how specific modification of HDAC1 by SUMO1, but not by SUMO2, facilitates HDAC1 degradation. Our findings reveal that SUMO1, but not SUMO2, conjugation to HDAC1 promotes HDAC1 ubiquitination and degradation. This is suggested by the observation that in non-tumorigenic mammary epithelial cells HDAC1 is preferentially conjugated to SUMO1 leading to HDAC1 proteolysis, whereas in breast cancer cells HDAC1 is more conjugated to SUMO2, promoting HDAC1 protein stability. SUMO E3 ligases play an important role in paralog-specific conjugation; in particular, the SUMO E3 ligase PIASy, which is overexpressed in breast cancer cells, selectively promotes the conjugation of HDAC1 to SUMO2. Therefore, cell environment affects paralog-specific sumoylation of HDAC1, whose conjugation to SUMO1 but not to SUMO2 facilitates its protein turnover. Our findings uncover a role for paralog-specific sumoylation of HDAC1 whose significance is emphasized by the use of HDAC inhibitors as anticancer drugs.