Potential Therapeutic Use of Aptamers against HAT1 in Lung Cancer

SIMPLE SUMMARY: Lung cancer is one of the leading causes of death worldwide and the most common of all cancer types. Histone acetyltransferase 1 (HAT1) has attracted increasing interest as a potential therapeutic target due to its involvement in multiple pathologies, including cancer. Aptamers are single-stranded RNA or DNA molecules whose three-dimensional structure allows them to bind to a target molecule with high specificity and affinity, thus making them exceptional candidates for use as diagnostic or therapeutic tools. In this work, aptamers against HAT1 were obtained, subsequently characterized, and optimized, showing high affinity and specificity for HAT1 and the ability to inhibit acetyltransferase activity in vitro. Of those tested, the apHAT610 aptamer reduced cell viability, induced apoptosis and cell cycle arrest, and inhibited colony formation in lung cancer cell lines. All these results indicate that the apHAT610 aptamer is a potential drug for the treatment of lung cancer. ABSTRACT: Lung cancer is one of the leading causes of death worldwide and the most common of all cancer types. Despite scientific advances in recent years, which have led to the development of new diagnostic and therapeutic approaches, the search for new treatments and early diagnosis of the disease remains an absolute necessity in oncology. Histone acetyltransferase 1 (HAT1) belongs to the HAT family of enzymes and has attracted increasing interest in recent years due to its involvement in multiple pathologies. HAT1 overexpression is related, among other outcomes, to viral infections, inflammatory diseases, and cancer, where it is associated with poor prognosis and low survival. Therefore, many authors propose HAT1 as a potential therapeutic target. Aptamers are single-stranded RNA or DNA molecules whose three-dimensional structures allow them to bind to a target molecule with high specificity and affinity. This makes them exceptional candidates for use as diagnostic or therapeutic tools, among other applications. In this work, aptamers against HAT1 were obtained from oligonucleotide libraries using the systematic evolution of ligands through the exponential enrichment (SELEX) approach. After six rounds of screening, two specific aptamers were obtained and subsequently characterized and optimized. Both aptamers and one derivative based on modified sequences recognized HAT1 with high affinity and specificity and were able to inhibit the acetyltransferase activity of HAT1 in vitro. Furthermore, application of the apHAT610 aptamer resulted in reduced cell viability, induced apoptosis and cell cycle arrest, and inhibited colony formation in lung cancer cell lines. In addition, the apHAT610 aptamer inhibited HAT1 activity in these three cell lines, thus promoting a decrease in histone H4 acetylation and HAT1 protein levels. All these results indicate that the apHAT610 aptamer is a potential drug for the treatment of lung cancer.