RESUMEN
Clinical and pre-clinical work for a number of cancer types has demonstrated relatively positive outcomes and effective tumour regression when the level and function of p53, a well-established tumour suppressor, is restored. Human papillomavirus (HPV)-driven cancers encode the E6 oncoprotein, which leads to p53 degradation, to allow the carcinogenic process to proceed. Indeed, there have been several attempts to revive p53 function in HPV-driven cancers by both pharmacological and genetic means to increase p53 bioavailability. Here, we employed a CRISPR activation (CRISPRa) approach to overcome HPV-mediated silencing of p53 by hyperexpressing the p53 gene promoter. Our data show that CRISPRa-mediated hyperexpression of p53 leads to HPV+ cervical cancer cell killing and the reduction of cell proliferation. This proof-of-concept data suggest that increasing p53 bioavailability may potentially be a promising therapeutic approach for the treatment of HPV-driven cancers.
Asunto(s)
Proteínas Oncogénicas Virales , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Femenino , Humanos , Neoplasias del Cuello Uterino/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Virus del Papiloma Humano , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/genética , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Proteínas Oncogénicas Virales/genética , Proteínas Oncogénicas Virales/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/metabolismoRESUMEN
Despite a vaccine being available, human papillomavirus virus (HPV)-driven cancers remain the ninth most prevalent cancers globally. Current therapies have significant drawbacks and often still lead to poor prognosis and underwhelming survival rates. With gene therapy becoming more available in the clinic, it poses a new front for therapeutic development. A characteristic of HPV-driven cancers is the ability to encode oncoproteins that aberrate normal p53 function without mutating this tumour-suppressor gene. The HPV E6 oncoprotein degrades p53 to allow the HPV-driven carcinogenic process to proceed. This review aimed to investigate the use of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing technology and how it may be used to overcome HPV-mediated silencing of p53 by hyper-expressing the p53 promoter. Increasing p53 bioavailability may have promising potential as a therapy and has been a goal in the context of HPV-driven cancers. Clinical trials and proof-of-concept pre-clinical work have shown positive outcomes and tumour death when p53 levels are increased. Despite previous successes of RNA-based medicines, including the knockout of HPV oncogenes, the use of CRISPR activation is yet to be investigated as a promising potential therapy. This short review summarises key developments on attempts that have been made to increase p53 expression in the context of HPV cancer therapy, but leaves open the possibility for other cancers bearing a p53 wild-type gene.
