SUMO pathway components as possible cancer biomarkers

Mattoscio, Domenico; Chiocca, Susanna

doi:10.2217/fon.15.41

Cited by 33 publications

(31 citation statements)

References 107 publications

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“…In agreement with this hypothesis, we showed that UBC9 expression finely regulates HKs apoptosis (Fig 4C and 4D) similarly to what previously found in other systems [22,25,56]. Indeed, the essential SUMO conjugating enzyme UBC9 is a central protein for many cellular activities and could also be a fundamental driver of cancer growth since it is altered in a variety of human malignancies [21], and thus a putative candidate for drug therapy [57]. Our results strengthen this view and extend the potential use of targeting UBC9 also to induce death in HPV-transduced cells (Fig 4C), usually very resistant to apoptosis [31], in order to facilitate their clearance.…”

Section: Discussionsupporting

confidence: 90%

“…Moreover, in addition to its crucial involvement in SUMOylation, UBC9 may also function as a molecular chaperone [14], protein stabilizer [15], or as transcriptional [16] and miRNAs regulator [17]. Accordingly to its pleiotropic role, UBC9 is frequently targeted by numerous viral proteins [18–20] and is often altered in cancers, substantially contributing to the development of human malignancies (see [21] for a recent review). Indeed, recent evidence pinpoints to UBC9 as an important enzyme in human tumorigenesis since its selective targeting may easily subvert a variety of physiological pathway to support cancer growth.…”

Section: Introductionmentioning

confidence: 99%

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Autophagy regulates UBC9 levels during viral-mediated tumorigenesis

et al. 2017

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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.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Autophagy regulates UBC9 levels during viral-mediated tumorigenesis

et al. 2017

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“…SUMOylation is a key post-translational modification that regulates crucial cellular functions and pathological processes, and is a driver in human tumorigenesis [34]. SUMOylation may affect several aspects of a target protein, including stability, localization and activity [18].…”

Section: Discussionmentioning

confidence: 99%

SUMOylated MAFB promotes colorectal cancer tumorigenesis

et al. 2016

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The transcription factor, v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB), promotes tumorigenesis in some cancers. In this study, we found that MAFB levels were increased in clinical colorectal cancer (CRC) samples, and higher expression correlated with more advanced TNM stage. We identified MAFB amplifications in a majority of tumor types in an assessment of The Cancer Genome Atlas database. Altered MAFB levels due to gene amplification, deletion, mutation, or transcription upregulation occurred in 9% of CRC cases within the database. shRNA knockdown experiments demonstrated that MAFB deficiency blocked CRC cell proliferation by arresting the cell cycle at G0/G1 phase in vitro. We found that MAFB could be SUMOylated by SUMO1 at lysine 32, and this modification was critical for cell cycle regulation by MAFB in CRC cells. SUMOylated MAFB directly regulated cyclin-dependent kinase 6 transcription by binding to its promoter. MAFB knockdown CRC cell xenograft tumors in mice grew more slowly than controls, and wild-type MAFB-overexpressing tumors grew more quickly than tumors overexpressing MAFB mutated at lysine 32. These data suggest that SUMOylated MAFB promotes CRC tumorigenesis through cell cycle regulation. MAFB and its SUMOylation process may serve as novel therapeutic targets for CRC treatment.

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“…Other potential biomarkers include the use of EGFR mutations [17], SUMO pathway components [18], and genomic characteristics of tumors [19, 20], to name but a few. However, all of the above-named biomarkers require biopsy tissue for either histological or genetic analysis, and many require primary tumor samples for analysis.…”

Section: Introductionmentioning

confidence: 99%

Using lymph node swelling as a potential biomarker for successful vaccination

Brewer¹,

DeBay²,

Dude³

et al. 2016

Oncotarget

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There is currently a lack of biomarkers to help properly assess novel immunotherapies at both the preclinical and clinical stages of development. Recent work done by our group indicated significant volume changes in the vaccine draining right lymph node (RLN) volumes of mice that had been vaccinated with DepoVaxTM, a lipid-based vaccine platform that was developed to enhance the potency of peptide-based vaccines. These changes in lymph node (LN) volume were unique to vaccinated mice.To better assess the potential of volumetric LN markers for multiple vaccination platforms, we evaluated 100 tumor bearing mice and assessed their response to vaccination with either a DepoVax based vaccine (DPX) or a water–in-oil emulsion (w/o), and compared them to untreated controls. MRI was used to longitudinally monitor LN and tumor volumes weekly over 4 weeks. We then evaluated changes in LN volumes occurring in response to therapy as a potential predictive biomarker for treatment success.We found that for both vaccine types, DPX and w/o, the %RLN volumetric increase over baseline and the ratio of RLN/LLN were strong predictors of successful tumor suppression (LLN is left inguinal LN). The area under the curve (AUC) was greatest, between 0.75-0.85, two (%RLN) or three (RLN/LLN) weeks post-vaccination. For optimized critical thresholds we found these biomarkers consistently had sensitivity >90% and specificity >70% indicating strong prognostic potential. Vaccination with DepoVax had a more pronounced effect on draining lymph nodes than w/o emulsion vaccines, which correlated with a higher anti-tumor activity in DPX-treated mice.

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SUMO pathway components as possible cancer biomarkers

Cited by 33 publications

References 107 publications

Autophagy regulates UBC9 levels during viral-mediated tumorigenesis

Autophagy regulates UBC9 levels during viral-mediated tumorigenesis

SUMOylated MAFB promotes colorectal cancer tumorigenesis

Using lymph node swelling as a potential biomarker for successful vaccination

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