Post-Transcriptional Gene Regulation by HPV 16E6 and Its Host Protein Partners

Abstract

Human papillomavirus type 16 (HPV 16) is the most common oncogenic type of HPV in cervical, anogenital, and head and neck cancers, making HPV 16 an important high-risk HPV (HR HPV) type. To create an environment permissible for viral maintenance and growth and to initiate and support oncogenesis, the HR HPV protein E6 functions to dysregulate normal cellular processes. HR HPV type 16 E6 (16E6) has previously been shown to bind cellular proteins in order to transcriptionally activate genes and to target regulatory proteins for degradation. We have identified an additional functional model for 16E6. First, 16E6 binds to cellular RNA processing and binding proteins, specifically cytoplasmic poly(A) binding proteins (PABPCs) and NFX1-123. Then, 16E6 hijacks those proteins’ functions to post-transcriptionally regulate cellular immortalization, growth, and differentiation genes and pathways in keratinocytes. In this review, we have highlighted studies that introduce this new model of 16E6 functionality. Understanding ways in which HR HPV dysregulates cellular processes—particularly at the level of post-transcriptional gene regulation—presents new ways to consider mechanisms underlying DNA tumor virus function and new areas for therapeutic target development in HPV-associated cancers.

NFX1‐123: A potential therapeutic target in cervical cancer

“…The binding sites and modeled amino acid‐drug positions of the top four drug compounds with NFX1‐123 were visualized (Figure 2C). Of note, the binding amino acids positions ASP‐849 of Ropitoin, ASP‐849 and LYS‐853 of R428, and ASP‐849 of Perospirone are unique to the NFX1‐123 splice variant as they are not present in the shorter NFX1 isoform, NFX1‐91 1,3 . These drug compounds were then tested in cell‐based assays to determine if they could bind to, and affect, the NFX1‐123 protein itself or affect its targeted function.…”

“…Previous studies have determined that 16E6 and NFX1‐123 together shifted the normal localization of signaling proteins involved in the innate immune response's activation, 2 a critical step in immune evasion by HPV. Additionally, 16E6 utilized NFX1‐123 to affect cellular growth, differentiation, and immortalization genes and pathways through posttranscriptional gene regulation, 1,3–8 affecting multiple pathways important in HPV‐associated oncogenesis.…”

Overexpression of the telomerase holoenzyme induces EMT and tumorigenesis of HPV‐immortalized keratinocytes

“…42 Studies also have shown that E6 induces TERT promoter activation by interacting with transcription factors, Myc, Max, Mad and SP1. 22,43,44 It is likely that in our cells E6 cooperates with a splice variant of NFX1-91, namely NFX1-123, to cause the increase in telomerase activity through the posttranscriptional stabilization of TERT mRNA (Billingsley et al 45 ;…”

The Molecular Interplay between Human Oncoviruses and Telomerase in Cancer Development

“…The NFX1-91 interacts with the mSin3A-histone deacetylase complex and its removal causes the overexpression of histone acetyltransferase, the increase of histone protein acetylation and enhancement of TERT transcription [73]. The HPV16 E6 has also been demonstrated to cooperate with a splice variant of NFX1-91, namely NFX1-123, as well as with cellular RNA processing proteins, such as cytoplasmic poly(A) binding proteins (PABPCs), and to cause the increase of telomerase activity through the post-transcriptional stabilization of TERT mRNA in human keratinocytes [74,75]. The study of NFX1-123 transcripts in biological samples showed that it is highly expressed in cervical precancer lesions, invasive carcinoma and derived cell lines [76].…”