The low-density lipoprotein receptor-related protein (LRP1B), encoding an endocytic LDL-family receptor, is among the 10 most significantly deleted genes across 3312 human cancer specimens. However, currently the apparently crucial role of this lipoprotein receptor in carcinogenesis is not clear. Here we show that LRP1B inactivation (by chromosomal, epigenetic and microRNA (miR)-mediated mechanisms) results in changes to the tumor environment that confer cancer cells an increased growth and invasive capacity. LRP1B displays frequent DNA copy number loss and CpG island methylation, resulting in mRNA underexpression. By using CpG island reporters methylated in vitro, we found that DNA methylation disrupts a functional binding site for the histone-acetyltransferase p300 located at intron 1. We identified and validated an miR targeting LRP1B (miR-548a-5p), which is overexpressed in cancer cell lines as a result of 8q22 DNA gains. Restoration of LRP1B impaired in vitro and in vivo tumor growth, inhibited cell invasion and led to a reduction of matrix metalloproteinase 2 in the extracellular medium. We emphasized the role of an endocytic receptor acting as a tumor suppressor by modulating the extracellular environment composition in a way that constrains the invasive behavior of the cancer cells.

The role of epigenetic modifications on the carcinogenesis process has received a lot of attention in the last years. Among those, histone acetylation is a process regulated by histone deacetylases (HDAC) and histone acetyltransferases (HAT), and it plays an important role in epigenetic regulation, allowing the control of the gene expression. HDAC inhibitors (HDACi) induce cancer cell cycle arrest, differentiation, and cell death and reduce angiogenesis and other cellular events. Human papillomaviruses (HPVs) are small, non-enveloped double-stranded DNA viruses. They are major human carcinogens, being intricately linked to the development of cancer in 4.5% of the patients diagnosed with cancer worldwide. Long-term infection of high-risk (HR) HPV types, mainly HPV16 and HPV18, is one of the major risk factors responsible for promoting cervical cancer development. In vitro and in vivo assays have demonstrated that HDACi could be a promising therapy to HPV-related cervical cancer. Regardless of some controversial studies, the therapy with HDACi could target several cellular targets which HR-HPV oncoproteins could be able to deregulate. This review article describes the role of HDACi as a possible intervention in cervical cancer treatment induced by HPV, highlighting the main advances reached in the last years and providing insights for further investigations regarding those agents against cervical cancer.

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Cervical cancer (CC) is the fourth most common pathology in women worldwide and presents a high impact in developing countries due to limited financial resources as well as difficulties in monitoring and access to health services. Human papillomavirus (HPV) is the leading cause of CC, and despite the approval of prophylactic vaccines, there is no effective treatment for patients with pre-existing infections or HPV-induced carcinomas. High-risk (HR) HPV E6 and E7 oncoproteins are considered biomarkers in CC progression. Since the E6 structure was resolved, it has been one of the most studied targets to develop novel and specific therapeutics to treat/manage CC. Therefore, several small molecules (plant-derived or synthetic compounds) have been reported as blockers/inhibitors of E6 oncoprotein action, and computational-aided methods have been of high relevance in their discovery and development. In silico approaches have become a powerful tool for reducing the time and cost of the drug development process. Thus, this review will depict small molecules that are already being explored as HR HPV E6 protein blockers and in silico approaches to the design of novel therapeutics for managing CC. Besides, future perspectives in CC therapy will be briefly discussed.