Activation of DNA damage repair factors in HPV positive oropharyngeal cancers

Kono, Takeyuki; Hoover, Paul; Poropatich, Kate; Paunesku, Tatjana; Mittal, Bharat B.; Samant, Sandeep; Laimins, Laimonis A.

doi:10.1016/j.virol.2020.05.003

Cited by 18 publications

(15 citation statements)

References 44 publications

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“…1C). While HPV infection itself may activate DNA damage repair factors (20), the basal amount of DNA damage (γH2AX) was not increased in UM-SCC47 cells (HPV+) compared to HPVnegative cells, but WEE1i treatment caused the largest relative increase in γH2AX in HPV+ UM-SCC47 cells (SI Appendix, Fig. S1 B-D).…”

Section: Resultsmentioning

confidence: 99%

FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition

Diab

Gem

Swanger

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Head and neck squamous cell carcinoma (HNSCC) associated with high-risk human papilloma virus (HPV) infection is a growing clinical problem. The WEE1 kinase inhibitor AZD1775 (WEE1i) overrides cell cycle checkpoints and is being studied in HNSCC regimens. We show that the HPV16 E6/E7 oncoproteins sensitize HNSCC cells to single-agent WEE1i treatment through activation of a FOXM1-CDK1 circuit that drives mitotic gene expression and DNA damage. An isogenic cell system indicated that E6 largely accounts for these phenotypes in ways that extend beyond p53 inactivation. A targeted genomic analysis implicated FOXM1 signaling downstream of E6/E7 expression and analyses of primary tumors and The Cancer Genome Atlas (TCGA) data revealed an activated FOXM1-directed promitotic transcriptional signature in HPV+ versus HPV- HNSCCs. Finally, we demonstrate the causality of FOXM1 in driving WEE1i sensitivity. These data suggest that elevated basal FOXM1 activity predisposes HPV+ HNSCC to WEE1i-induced toxicity and provide mechanistic insights into WEE1i and HPV+ HNSCC therapies.

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Section: Resultsmentioning

confidence: 99%

FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition

Diab

Gem

Swanger

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…More evidence supporting a pro-tumorigenic role of APOBEC comes from immunohistochemistry and reverse transcription quantitative PCR analyses reporting higher expression levels of A3A and A3B in HPV + vs. HPV - HNSCCs [ 12 , 87 , 89 ], with only one immunofluorescence-based study failing to detect enhanced A3 protein expression in HPV + oropharyngeal cancers [ 91 ]. In particular, RT-qPCR of samples from tumor tissues and healthy mucosa showed low mRNA expression levels of A3A and A3B in HPV - HNSCC, whereas their expression was upregulated by 2–100 folds in HPV + cancers [ 12 ].…”

Section: The Role Of Apobec In Hnsccmentioning

confidence: 99%

HPV Meets APOBEC: New Players in Head and Neck Cancer

Riva

Albano

Gugliesi

et al. 2021

IJMS

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Besides smoking and alcohol, human papillomavirus (HPV) is a factor promoting head and neck squamous cell carcinoma (HNSCC). In some human tumors, including HNSCC, a number of mutations are caused by aberrantly activated DNA-modifying enzymes, such as the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) family of cytidine deaminases. As the enzymatic activity of APOBEC proteins contributes to the innate immune response to viruses, including HPV, the role of APOBEC proteins in HPV-driven head and neck carcinogenesis has recently gained increasing attention. Ongoing research efforts take the cue from two key observations: (1) APOBEC expression depends on HPV infection status in HNSCC; and (2) APOBEC activity plays a major role in HPV-positive HNSCC mutagenesis. This review focuses on recent advances on the role of APOBEC proteins in HPV-positive vs. HPV-negative HNSCC.

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“…Several studies have suggested a linkage between DDR pathways and APOBECs. The repair of DNA breaks by the ATR pathway often generates ssDNAs which can be targeted by APOBECs [ 85 , 86 , 87 ]. Treatment of cancer cells with either ATM or ATR inhibitors leads to a reduction in the levels of APOBEC3 activation [ 88 ].…”

Section: Apobecs and Hpv Positive Lesionsmentioning

confidence: 99%

“…Furthermore, treatment with CHK1 inhibitors reduced the levels of APOPEC3B transcription [ 89 ] while increased expression of APBEC3A leads to enhanced levels of DNA breaks and γH2AX [ 90 ]. Activation of DDR pathways in HPV positive cells also corelates closely with increased levels of APOBEC3B [ 85 ]. In particular, components of ATR and FA pathways are increased HPV positive OPSCCC cells that also contain enhanced levels of APOBEC3B as compared to HPV negative cancers and normal cells.…”

Section: Apobecs and Hpv Positive Lesionsmentioning

confidence: 99%

“…In particular, components of ATR and FA pathways are increased HPV positive OPSCCC cells that also contain enhanced levels of APOBEC3B as compared to HPV negative cancers and normal cells. This suggests a possible linkage between APOBEC3B and DDR activation in HPV positive cells [ 85 ]. Although APOBEC3 proteins can function as antiviral factors, the high levels of APOBEC3 detected in cells that stably express HPV proteins suggest they may have a positive role in viral pathogenesis and is an area for future study.…”

Section: Apobecs and Hpv Positive Lesionsmentioning

confidence: 99%

See 1 more Smart Citation

Genomic Instability and DNA Damage Repair Pathways Induced by Human Papillomaviruses

Kono

Laimins

2021

Viruses

Self Cite

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Human papillomaviruses (HPV) are the causative agents of cervical and other anogenital cancers as well as those of the oropharynx. HPV proteins activate host DNA damage repair factors to promote their viral life cycle in stratified epithelia. Activation of both the ATR pathway and the ATM pathway are essential for viral replication and differentiation-dependent genome amplification. These pathways are also important for maintaining host genomic integrity and their dysregulation or mutation is often seen in human cancers. The APOBEC3 family of cytidine deaminases are innate immune factors that are increased in HPV positive cells leading to the accumulation of TpC mutations in cellular DNAs that contribute to malignant progression. The activation of DNA damage repair factors may corelate with expression of APOBEC3 in HPV positive cells. These pathways may actively drive tumor development implicating/suggesting DNA damage repair factors and APOBEC3 as possible therapeutic targets.

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Activation of DNA damage repair factors in HPV positive oropharyngeal cancers

Cited by 18 publications

References 44 publications

FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition

FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition

HPV Meets APOBEC: New Players in Head and Neck Cancer

Genomic Instability and DNA Damage Repair Pathways Induced by Human Papillomaviruses

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