The PKC/NF-κB Signaling Pathway Induces APOBEC3B Expression in Multiple Human Cancers

Leonard, Brandon; McCann, John D.; Starrett, Gabriel J.; Kosyakovsky, Leah; Luengas, Elizabeth M.; Molan, Amy M.; Burns, Michael B.; McDougle, Rebecca M.; Parker, Peter J.; Brown, William L.; Harris, Reuben S.

doi:10.1158/0008-5472.can-15-2171-t

Cited by 119 publications

(150 citation statements)

References 47 publications

Supporting

Mentioning

136

Contrasting

Order By: Relevance

“…5I and J), which continuously express E6 and E7. We speculate that TEAD-mediated A3B upregulation occurs in the early stages of HPV-induced cervical carcinogenesis, whereas the A3B expression in advanced cancer cells is switched to being dependent on the NF-B pathway, as recently reported for breast cancer cells (15), although this hypothesis awaits further experimental verification.…”

Section: Figsupporting

confidence: 62%

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

Mori

Takeuchi

Ishii

et al. 2017

J Virol

View full text Add to dashboard Cite

The cytidine deaminase APOBEC3B (A3B) underlies the genetic heterogeneity of several human cancers, including cervical cancer, which is caused by human papillomavirus (HPV) infection. We previously identified a region within the A3B promoter that is activated by the viral protein HPV16 E6 in human keratinocytes. Here, we discovered three sites recognized by the TEAD family of transcription factors within this region of the A3B promoter. Reporter assays in HEK293 cells showed that exogenously expressed TEAD4 induced A3B promoter activation through binding to these sites. Normal immortalized human keratinocytes expressing E6 (NIKS-E6) displayed increased levels of TEAD1/4 protein compared to parental NIKS. A series of E6 mutants revealed that E6-mediated degradation of p53 was important for increasing TEAD4 levels. Knockdown of TEADs in NIKS-E6 significantly reduced A3B mRNA levels, whereas ectopic expression of TEAD4 in NIKS increased A3B mRNA levels. Finally, chromatin immunoprecipitation assays demonstrated increased levels of TEAD4 binding to the A3B promoter in NIKS-E6 compared to NIKS. Collectively, these results indicate that E6 induces upregulation of A3B through increased levels of TEADs, highlighting the importance of the TEAD-A3B axis in carcinogenesis.IMPORTANCE The expression of APOBEC3B (A3B), a cellular DNA cytidine deaminase, is upregulated in various human cancers and leaves characteristic, signature mutations in cancer genomes, suggesting that it plays a prominent role in carcinogenesis. Viral oncoproteins encoded by human papillomavirus (HPV) and polyomavirus have been reported to induce A3B expression, implying the involvement of A3B upregulation in virus-associated carcinogenesis. However, the molecular mechanisms causing A3B upregulation remain unclear. Here, we demonstrate that exogenous expression of the cellular transcription factor TEAD activates the A3B promoter. Further, the HPV oncoprotein E6 increases the levels of endogenous TEAD1/4 protein, thereby leading to A3B upregulation. Since increased levels of TEAD4 are frequently observed in many cancers, an understanding of the direct link between TEAD and A3B upregulation is of broad oncological interest.

show abstract

Section: Figsupporting

confidence: 62%

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

Mori

Takeuchi

Ishii

et al. 2017

J Virol

View full text Add to dashboard Cite

show abstract

“…26 In papillomas, NF-κβ and the axis of ROCK2/FAK/β-catenin 5,6 may contribute to the demise of p53, given both NF-κβ 26 and FAK-associated β-catenin 38,46 inhibit p53 expression. These papilloma data thus link NF-κβ with increased DNA mutations/chromosomal instability 25,39 following p53 loss and associated p21 inhibition 47 [below]; and indirectly link ROCK2-mediated NF-κβ to stromal remodelling 25 thus accounting for effects previously observed on expression of ECM molecules such as tenascin C. 48,49 One consequence of p53 loss leading to an altered matrix may involve downregulated microRNAs, 34 such as miR-200 which regulates cell-cell adhesion molecules 35 and effected ROCK signalling in gastric cancer. 36 Of note, p53-mediated miR-200 expression depended upon AKT levels, 37 consistent with p53 loss driving malignant conversion in trigenic HK1.ras/fos/Pten flx carcinogenesis.…”

Section: Discussionmentioning

confidence: 85%

“…47 Of relevance to K14.ROCK er /HK1.ras 1205 carcinogenesis, p21 overexpression protected NEMO Dhepa animals against DNA damage, 39,41 whereas p21 knockout accelerated hepato-carcinogenesis in bi-genic NEMO Dhepa /p21 null mice, 47 thus implicating NF-κβ in chromosomal damage. 33,39,41,45 Most major consequences of ROCK2 activation alter the tumour microenvironment and establish a context permissive for stage-specific progression. 1,2,13 Previous K14.ROCK er studies demonstrated ROCK-associated collagen deposition resulted in a stiffened ECM and increased tissue rigidity.…”

Section: Discussionmentioning

confidence: 99%

ROCK2/rasHa co-operation induces malignant conversion via p53 loss, elevated NF-κB and tenascin C-associated rigidity, but p21 inhibits ROCK2/NF-κB-mediated progression

et al. 2016

View full text Add to dashboard Cite

ROCK2/rasHa cooperation induce malignant conversion via p53 loss, elevated NF-κβ and tenascin C-associated rigidity but p21 inhibits ROCK2/NF-κβ-mediated progression. Oncogene, 36, pp. 2529Oncogene, 36, pp. -2542Oncogene, 36, pp. . (doi:10.1038Oncogene, 36, pp. /onc.2016 This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/129163/ Malignancy depended on ROCK er /p-Mypt1 expression, as cessation of 4HT-treatment induced disorganised tissue architecture and p21-associated differentiation in wdSCCs; yet tenascin C retention in connective tissue ECM suggests the rigidity laid down for conversion persists. Novel papilloma outgrowths appeared expressing intense, basal-layer p21 which confined endogenous ROCK2/p-Mypt1/NF-κβ to supra-basal layers, and was paralleled by restored basal-layer p53. In later SCCs, 4HT-cessation became irrelevant as endogenous ROCK2 expression increased, driving progression via p21 loss, elevated NF-κβ expression and tenascin C-associated rigidity; with p-Mypt1 inactivation/actinomyosin-mediated contractility to facilitate invasion. However, p21-associated inhibition of early-stage malignant progression and the intense expression in papilloma outgrowths, identifies a novel, significant antagonism between p21 and ras Ha /ROCK2/NF-κβ signalling in skin 3 carcinogenesis. Collectively these data show that ROCK2 activation induces malignancy in ras Ha -initiated/promoted papillomas in the context of p53 loss and novel NF-κβ expression; whilst increased tissue rigidity and cell motility/contractility help mediate tumour progression.4

show abstract

“…a rabbit monoclonal antibody used at a dilution of 1:50 (30). This antibody recognizes both A3B and A3G; however, the two proteins can be distinguished by differential gel migration (30; this study).…”

Section: Verhalen Et Almentioning

confidence: 99%

Functional Upregulation of the DNA Cytosine Deaminase APOBEC3B by Polyomaviruses

Verhalen

Starrett

Harris

et al. 2016

J Virol

Self Cite

106

View full text Add to dashboard Cite

The APOBEC3 family of DNA cytosine deaminases has important roles in innate immunity and cancer. It is unclear how DNA tumor viruses regulate these enzymes and how these interactions, in turn, impact the integrity of both the viral and cellular genomes. Polyomavirus (PyVs) are small DNA pathogens that contain oncogenic potentials. In this study, we examined the effects of PyV infection on APOBEC3 expression and activity. We demonstrate that APOBEC3B is specifically upregulated by BK polyomavirus (BKPyV) infection in primary kidney cells and that the upregulated enzyme is active. We further show that the BKPyV large T antigen, as well as large T antigens from related polyomaviruses, is alone capable of upregulating APOBEC3B expression and activity. Furthermore, we assessed the impact of A3B on productive BKPyV infection and viral genome evolution. Although the specific knockdown of APOBEC3B has little short-term effect on productive BKPyV infection, our informatics analyses indicate that the preferred target sequences of APOBEC3B are depleted in BKPyV genomes and that this motif underrepresentation is enriched on the nontranscribed stand of the viral genome, which is also the lagging strand during viral DNA replication. Our results suggest that PyV infection upregulates APOBEC3B activity to influence virus sequence composition over longer evolutionary periods. These findings also imply that the increased activity of APOBEC3B may contribute to PyV-mediated tumorigenesis. IMPORTANCEPolyomaviruses (PyVs) are a group of emerging pathogens that can cause severe diseases, including cancers in immunosuppressed individuals. Here we describe the finding that PyV infection specifically induces the innate immune DNA cytosine deaminase APOBEC3B. The induced APOBEC3B enzyme is fully functional and therefore may exert mutational effects on both viral and host cell DNA. We provide bioinformatic evidence that, consistent with this idea, BK polyomavirus genomes are depleted of APOBEC3B-preferred target motifs and enriched for the corresponding predicted reaction products. These data imply that the interplay between PyV infection and APOBEC proteins may have significant impact on both viral evolution and virusinduced tumorigenesis. P olyomaviruses (PyVs) are a family of small nonenveloped viruses containing an ϳ5-kb circular double-stranded DNA genome. Most human PyVs establish a subclinical persistent infection in healthy individuals (1). These viruses can reactivate under various immunosuppression conditions and cause a variety of severe diseases, including cancers (2). Among them, BK polyomavirus (BKPyV) reactivation is a major concern in kidney and bone marrow transplant patients due to the possibility of development of polyomavirus-associated nephropathy and hemorrhagic cystitis, respectively (3). Recently, there have also been increasing reports demonstrating an association between BKPyV infection and the occurrence of renourinary tumors (4). JC polyomavirus (JCPyV) reactivation can lead to progressive multifocal leu...

show abstract

The PKC/NF-κB Signaling Pathway Induces APOBEC3B Expression in Multiple Human Cancers

Cited by 119 publications

References 47 publications

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

ROCK2/rasHa co-operation induces malignant conversion via p53 loss, elevated NF-κB and tenascin C-associated rigidity, but p21 inhibits ROCK2/NF-κB-mediated progression

Functional Upregulation of the DNA Cytosine Deaminase APOBEC3B by Polyomaviruses

Contact Info

Product

Resources

About