CDK9 Inhibitor FIT-039 Suppresses Viral Oncogenes E6 and E7 and Has a Therapeutic Effect on HPV-Induced Neoplasia

Ajiro, Masahiko; Sakai, Hiroyuki; Onogi, Hiroshi; Yamamoto, Makoto; Sumi, Eriko; Sawada, Teruo; Nomura, Takashi; Kabashima, Kenji; Hosoya, Takamitsu

doi:10.1158/1078-0432.ccr-17-3119

Cited by 31 publications

(29 citation statements)

References 47 publications

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“…Several viral proteins regulate P-TEFb (31,54). Recently, it was reported that the CDK9 inhibitor FIT-39 repressed HPV early promoter activity, resulting in reduction of E6 and E7 transcripts (36). From our experiments, we presume that both WT E2 and Y138F can compete with CDK9 for Brd4-CTD binding more favorably than Y138E, and we subsequently tested Y138E and Y138F for transcriptional activation.…”

Section: Discussionmentioning

confidence: 69%

Phosphorylation of a Conserved Tyrosine in the Papillomavirus E2 Protein Regulates Brd4 Binding and Viral Replication

DeSmet

Jose

Isaq

et al. 2019

J Virol

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The papillomavirus (PV) E2 protein coordinates viral transcription and genome replication. Following a strategy to identify amino acids in E2 that are posttranslationally modified, we reported that tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) complexes with and phosphorylates E2, which inhibits viral DNA replication. Here, we present several lines of evidence indicating that tyrosine (Y) 138 of HPV-31 E2 is a substrate of FGFR3. The active form of FGFR3 bound to and phosphorylated the region of amino acids (aa) 107 to 175 in HPV-31 E2. The E2 phenylalanine (F) mutant Y138F displayed reduced FGFR3-induced phosphotyrosine. A constitutive kinase-active FGFR3 inhibited wild-type (WT) E2-induced E1-dependent DNA replication, while the 138F mutant retained activity. The tyrosine to glutamic acid (E) mutant Y138E, which can mimic phosphotyrosine, failed to induce transient DNA replication, although it maintained the ability to bind and localize the viral DNA helicase E1 to the viral origin. The bromodomain-containing protein 4 (Brd4) binds to E2 and is necessary for initiation of viral DNA synthesis. Interestingly, the Y138E protein coimmunoprecipitated with full-length Brd4 but was defective for association with its C-terminal domain (CTD). These results imply that the activity of the FGFR3 kinase in the infected epithelial cell restricts the HPV replication program through phosphorylation of E2 at Y138, which interferes with E2 binding to the Brd4 CTD, and that this interaction is required for initiation of viral DNA synthesis. IMPORTANCE Human papillomaviruses (HPVs) are highly infectious pathogens that commonly infect the oropharynx and uterine cervix. The idea that posttranslational modifications of viral proteins coordinates viral genome replication is less explored. We recently discovered that fibroblast growth factor receptor 3 (FGFR3) phosphorylates the viral E2 protein. The current study demonstrates that FGFR3 phosphorylates E2 at tyrosine 138, which inhibits association with the C-terminal peptide of Brd4. This study illustrates a novel regulatory mechanism of virus-host interaction and provides insight into the role of Brd4 in viral replication.

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Section: Discussionmentioning

confidence: 69%

Phosphorylation of a Conserved Tyrosine in the Papillomavirus E2 Protein Regulates Brd4 Binding and Viral Replication

DeSmet

Jose

Isaq

et al. 2019

J Virol

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“…Although there exists continuous research concerning the tumorigenesis and development of endometrial cancer, it still remains unclear which signaling pathways or related molecules promote the occurrence and development of endometrial cancer. Many studies confirm that overexpression of cyclin-dependent kinase 9 (CDK9) is directly related to tumor development ( 13 – 19 ). A recent study found that CDK9 inhibition dephosphorylates the SWI/SNF protein BRG1 (ATP-dependent helicase) and reactivates epigenetic silenced genes in cancer, thereby restoring tumor-suppressor gene expression ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

“…CDK9 expression is significantly increased in different cellular processes and different tissues, and has an important contribution to the progression of various types of cancer (10). Recently, studies have found that CDK9 is of critical importance in the development of many cancers, including Targeting CDK9: A novel biomarker in the treatment of endometrial cancer leukemia, cervical cancer, prostate cancer, glioblastoma, breast cancer, melanoma and lung cancer (13)(14)(15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Targeting CDK9: A novel biomarker in�the�treatment of endometrial cancer

Fang

Xia

et al. 2020

Oncol Rep

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Endometrial cancer is one of the three major malignant tumors of the female reproductive system. Although cyclin-dependent kinase 9 (CDK9) has a definitive pathogenic role in various types of cancer, little is known concerning its function in endometrial cancer. Our study was conducted to evaluate the expression and therapeutic potential of CDK9 in endometrial cancer. CDK9 expression was determined by immunohistochemistry in endometrial cancer tissues constructed with paired primary, metastatic, and recurrent tumor tissues from 32 endometrial cancer patients. Small interfering RNA (siRNA) and inhibitors of CDK9 were used to evaluate the effect of CDK9 inhibition on the anti-apoptotic activity and proliferation in endometrial cancer cells. Colony formation assay and wound-healing assays were adopted to assess clonal formation and migratory capacity. The results of the immunohistochemistry demonstrated that CDK9 was highly expressed in the human endometrial cancer cell lines; moreover, it was elevated in metastatic and recurrent endometrial tumor tissue compared when compared with that in patient-matched primary endometrial tumor tissue. Knockdown of CDK9 with siRNA and inhibition of CDK9 activity with the inhibitor suppressed cell proliferation and promoted apoptosis in endometrial cancer. In conclusion, our results provide evidence that CDK9 may be a potential prognostic biomarker and a promising therapeutic target for the treatment of endometrial cancer in the future.

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“…More specifically, the CTD is phosphorylated by CDK7 on Ser 5 (s5) during transcription initiation and then on Ser 2 (s2) by CDK9 to promote transcriptional elongation (18). Recently, CDK9 has been shown to play crucial roles in many types of human cancer, including leukemia, cervical cancer, prostate cancer, glioblastoma, breast cancer, melanoma, and lung cancer (19)(20)(21)(22)(23)(24)(25). However, the relationship between CDK9 expression and clinical prognosis and the therapeutic potential of targeting CDK9 in ovarian cancer remains unclear.…”

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confidence: 99%

Cyclin‐dependent kinase 9 (CDK9) is a novel prognostic marker and therapeutic target in ovarian cancer

et al. 2019

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Despite surgical and chemotherapeutic advances over the past few decades, the prognosis for ovarian cancer remains very poor. Although cyclin‐dependent kinase (CDK) 9 has an established pathogenic role in various cancers, its function in ovarian cancer remains poorly defined. The purpose of this study was to evaluate the expression of CDK9 and its therapeutic potential in ovarian cancer. CDK9 expression was determined by immunohistochemistry in a unique ovarian cancer tissue microarray constructed with paired primary, metastatic, and recurrent tumor tissues from 26 ovarian cancer patients. CDK9 was highly expressed in human ovarian cancer cell lines and was also elevated in metastatic and recurrent ovarian tumor tissue compared with patient‐matched primary ovarian tumor tissue. In addition, increased CDK9 significantly correlated with poor patient prognosis. Inhibition of CDK9 by small interfering RNA or CDK9 inhibitor functionally suppressed RNA transcription elongation, induced apoptosis, and reduced proliferation of ovarian cancer cells. Inhibition of CDK9 also suppressed ovarian cancer cell spheroid growth, clonogenicity formation, and migration activity. Our results reveal CDK9 as a novel prognostic biomarker and a promising therapeutic target for preventing metastasis and recurrence while also improving the overall clinical outcome for ovarian cancer patients.— Wang, J., Dean, D. C., Hornicek, F. J., Shi, H., Duan, Z. Cyclin‐dependent kinase 9 (CDK9) is a novel prognostic marker and therapeutic target in ovarian cancer. FASEB J. 33, 5990–6000 (2019). http://www.fasebj.org

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CDK9 Inhibitor FIT-039 Suppresses Viral Oncogenes E6 and E7 and Has a Therapeutic Effect on HPV-Induced Neoplasia

Cited by 31 publications

References 47 publications

Phosphorylation of a Conserved Tyrosine in the Papillomavirus E2 Protein Regulates Brd4 Binding and Viral Replication

Phosphorylation of a Conserved Tyrosine in the Papillomavirus E2 Protein Regulates Brd4 Binding and Viral Replication

Targeting CDK9: A novel biomarker in�the�treatment of endometrial cancer

Cyclin‐dependent kinase 9 (CDK9) is a novel prognostic marker and therapeutic target in ovarian cancer

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