FOXM1 and CKS1 - novel cellular targets of the HPV oncogenes

Abstract

Persistent infections with oncogenic types of human papillomaviruses (HPVs) cause cervical and other anogenital carcinomas as well as cancers of the head and neck regions and thereby contribute significantly to the global cancer burden. Despite the existence of efficient prophylactic vaccines, the worldwide number of HPV-related cancer cases is estimated to rise. It therefore remains an important task to further investigate and delineate the molecular mechanisms that underlie HPV-driven tumorigenesis, in specific the actions of the two viral oncogenes E6 and E7 which promote and sustain the malignant phenotype of HPV-positive cancers. This is also hoped to offer new opportunities for HPV-targeted therapeutic intervention. In the present study, the two host cell genes FOXM1 and CKS1B were identified as novel target genes of HPV E6 and E7. Interestingly, both FOXM1 and CKS1 have been described to possess oncogenic properties in different types of cancers. By stimulating their transcriptional promoters, E6 and E7 increased FOXM1 and CKS1 mRNA and protein levels in HPV-positive cells. The inhibition of the tumor suppressor p53 and the pocket protein family by E6 and E7, respectively, was determined to mediate the activation of FOXM1 and CKS1B. Hence, the disruption of the repressive DREAM complex by E6/E7 emerged as a likely mechanism involved in conveying HPV oncogene-induced promoter activation of FOXM1 and CKS1B. On the phenotypic level, the elevated level of CKS1 exerts pro-proliferative and senescence-suppressing effects in HPV-positive cancer cells. Furthermore, while not affecting proliferation per se, FOXM1 was shown to protect cervical cancer cells from the proliferation-suppressing effects of chemotherapy. In growth-arrested HPV-positive cells, neither FOXM1 nor CKS1 levels were found to decline, which would be in line with their activation by E6/E7 via DREAM disruption. Collectively, the results presented in this thesis contribute to a deeper understanding of HPV-driven carcinogenesis and decipher how the viral oncogenes E6 and E7 promote tumorigenesis through extensive modulation of the host cell’s molecular networks. They also provide evidence that interfering with FOXM1 or CKS1 expression or function could be an attractive future strategy for the therapy of HPV-induced cancers.