Role of enhancer of zeste homolog 2 polycomb protein and its significance in tumor progression and cell differentiation

Epigenetics is a branch of genetics that focuses on the heritable changes of DNA or associated proteins, other than DNA sequence variations, which carry information content during cell division [1,2]. These heritable changes are ascribed to chromatin, which constitutes the ultrastructure of DNA and whose modifications affect the genetic material functionality. Differences in chromatin structure have been associated to transcription regulation [3-5] and chromosome stability [6,7], affecting both gene’s information, expression and heritability. Noteworthy, these epigenetic modifications are involved in both transcriptional activation and repression, indicating their widespread role as modulators of gene expression in numerous biological processes [8,9]. Chromatin is subjected to numerous modifications roughly classified in two groups: DNA and histone post-translational modifications (histone-PTMs). DNA methylation is the most studied epigenetic modification of DNA and corresponds to the covalent addition of a methyl (CH3) group to the nucleotide cytosine within CG dinucleotides or CNG trinucleotides where N can be C, A, G or T. Usually, DNA methylation induces decreased protein-DNA binding of transcription factors and leads to the repression of gene expression [10]. DNA “methylable” sequences are not uniform across the human genome but restricted in CpG rich DNA regions termed CpG islands (CGI). CGI are localized at repetitive sequences, heavy methylated, to prevent the reactivation of endoparasitic sequences such as transposons, and at gene promoter sequences, which are normally refractory to methylation in normal somatic cells [8,11].</br

Papilloomiviiruse transkriptsiooni ja regulaatorvalgu E2 uurimine

Väitekirja elektrooniline versioon ei sisalda publikatsioonePapilloomiviirused on viiruste perekond, mis nakatab nii inimeste kui loomade epiteelrakke ja põhjustab papilloome ehk näsakasvajaid, mis võivad teatud tingimustes areneda halvaloomulisteks kasvajateks. Inimese papilloomiviiruseid on teada üle 200 tüübi ja nad jagatakse kaheks grupiks nende koespetsiifilisuse alusel: limaskesti nakatavad papilloomiviirused ja naharakke nakatavad papilloomiviirused. Naha papilloomiviirused on siiani pälvinud vähem tähelepanu, sest nende võimalik seos nahakasvajatega on tulnud ilmsiks alles viimasel kümnendil. Meie keskendusime oma töös naha papilloomiviirusele HPV5, mida on viimasel ajal hakatud seostama nahakasvajate tekkega, aga mida on siiani ikkagi suhteliselt vähe uuritud. Meie töö tulemusena valmis HPV5 transkriptsiooni kaart, mille iseloomustamiseks me kasutasime inimese sääreluu kasvaja rakuliini U2OS. Selle rakuliini abil õnnestus meil kirjeldada 14 erinevat viiruse mRNAd. Edasises töös keskendusime viirusvalgu E2 uurimisele, mis on põhiline viiruse elutsükli regulaator. E2 valgul on lisaks täispikale valgule veel kaks isovormi, valgu C-terminaalset osa sisaldav E2C ja alternatiivse splaissinguga saadud E8/E2. Me uurisime E2 paiknemist rakus ja leidsime, et lühike E8 valgu järjestus on piisav selleks, et valk suunata raku tuuma. Meile teadaolevalt on see järjestus lühim tuuma suunav järjestus, mis on siiani teada. Tänu proteoomika arengule on siiani leitud üle 200 E2 partnervalgu, millest enamuse funktsioon viiruse elutsüklis on siiani teadmata. Meie leidsime uue E2-ga seonduva rakulise valgu, milleks on tuumamüosiin 1. See on esimene müosiini perekonda kuuluv E2 partnervalk ja katsed näitasid, et tuumamüosiin 1 mõjutab HPV5 DNA paljunemist rakus.Cutaneous papillomaviruses infect human cutaneous epithelium and in most cases these infections pass without symptoms, but in some instances, they can cause lesions and induce squamous cell carcinomas. One of the most prevalent virus types detected in skin cancer is HPV5. We tried to bring through our work more understanding about the properties of these viruses and focused our attention to HPV5 and to the first part of its life-cycle in the cells. We wanted to characterize HPV5 more thoroughly at RNA level and managed to identify HPV transcription map. We also studied papillomavirus main regulator protein E2, which influences all main viral life events. We studied E2 localization in the cell and identified short nuclear targeting signal, that sends proteins to the nucleus. We also found new E2 interaction partner nuclear myosin 1, which influences HPV5 replication

Hypermethylated gene ANKDD1A is a candidate tumor suppressor that interacts with FIH1 and decreases HIF1α stability to inhibit cell autophagy in the glioblastoma multiforme hypoxia microenvironment.

Ectopic epigenetic mechanisms play important roles in facilitating tumorigenesis. Here, we first demonstrated that ANKDD1A is a functional tumor suppressor gene, especially in the hypoxia microenvironment. ANKDD1A directly interacts with FIH1 and inhibits the transcriptional activity of HIF1α by upregulating FIH1. In addition, ANKDD1A decreases the half-life of HIF1α by upregulating FIH1, decreases glucose uptake and lactate production, inhibits glioblastoma multiforme (GBM) autophagy, and induces apoptosis in GBM cells under hypoxia. Moreover, ANKDD1A is highly frequently methylated in GBM. The tumor-specific methylation of ANKDD1A indicates that it could be used as a potential epigenetic biomarker as well as a possible therapeutic target

Oncolytic herpes viruses, chemotherapeutics, and other cancer drugs

Oncolytic viruses are emerging as a potential new way of treating cancers. They are selectively replication-competent viruses that propagate only in actively dividing tumor cells but not in normal cells and, as a result, destroy the tumor cells by consequence of lytic infection. At least six different oncolytic herpes simplex viruses (oHSVs) have undergone clinical trials worldwide to date, and they have demonstrated an excellent safety profile and intimations of efficacy. The first pivotal Phase III trial with an oHSV, talimogene laherparepvec (T-Vec [OncoVex&lt;sup&gt;GM-CSF&lt;/sup&gt;]), is almost complete, with extremely positive early results reported. Intuitively, therapeutically beneficial interactions between oHSV and chemotherapeutic and targeted therapeutic drugs would be limited as the virus requires actively dividing cells for maximum replication efficiency and most anticancer agents are cytotoxic or cytostatic. However, combinations of such agents display a range of responses, with antagonistic, additive, or, perhaps most surprisingly, synergistic enhancement of antitumor activity. When synergistic interactions in cancer cell killing are observed, chemotherapy dose reductions that achieve the same overall efficacy may be possible, resulting in a valuable reduction of adverse side effects. Therefore, the combination of an oHSV with “standard-of-care” drugs makes a logical and reasonable approach to improved therapy, and the addition of a targeted oncolytic therapy with “standard-of-care” drugs merits further investigation, both preclinically and in the clinic. Numerous publications report such studies of oncolytic HSV in combination with other drugs, and we review their findings here. Viral interactions with cellular hosts are complex and frequently involve intracellular signaling networks, thus creating diverse opportunities for synergistic or additive combinations with many anticancer drugs. We discuss potential mechanisms that may lead to synergistic interactions

An evaluation of the efficacy of adenovirus-mediated gene therapy with p53 for the treatment of cancer

Cancer is the second leading cause of mortality in the United States today, and equally prevalent throughout the world. Traditional treatments such as chemotherapy and radiotherapy have thus far proven unable to treat the disease with high efficacy, with different cancer types often requiring different treatments providing a spectrum of results. Cancer types in the late stages often have no adequate treatment at all. Over the past two decades, research in the field of gene therapy has created new hope in finding a remedy for cancer that displays a high efficacy in treating many different types and stages. The p53 tumor suppressor gene has garnered a great deal of interest, as p53 mutation or inactivation is present in approximately 50% of all cancers. The loss of p53 activity can be attributed to several different causes, including mutation of the p53 gene or overexpression of p53 inhibitors. Research has illustrated that the p53 protein plays an important role in tumor suppression by inducing senescence, cell cycle arrest, or cell apoptosis. Studies have shown that reactivation of p53 in tumor cells leads to tumor cell apoptosis and overall tumor regression. The focus of p53 research has now shifted to strategies of reintroducing or reactivating the gene in tumor cells so that it may carry out its anti-tumor functions. Of the strategies proposed, the use of adenovirus to introduce p53 shows the most promise. Adenoviruses bind to and enter the cell, and, after escaping proteasomal degradation, travel to the nucleus where they inject their genetic material. By delivering wild-type p53 gene into tumor cells using adenovirus, large amounts of p53 protein are transcribed in the cell and initiate its antitumor properties. Many clinical trials using adenovirus-mediated p53 gene transfer (Ad-p53) have been performed with generally positive results across a variety of cancer types. Ad-p53 in combination with more traditional treatments like chemotherapy and radiotherapy has been especially promising. The engineering of both adenoviral vectors and the p53 gene to be delivered presents new options for further increasing the efficacy of this therapeutic approach. Both Onyx-015, a selectively replicating adenovirus, and Ad-p53vp, a p53 gene that avoids inhibition, have been used in clinical trials with success. As a whole the field of adenovirus-mediate p53 gene transfer is promising and holds many advantages to classical treatments, but is still in the early stages of research. Further research must be completed so this therapy may be widely approved and used. The specific combination of Ad-p53 and traditional therapies has proven highly effective and should be used in clinical settings immediately

A Novel Approach of Virotherapy Based Hsf-1 Shrna in Cancer Eradication

Cancer is the second leading cause of death worldwide with continues rise mortality rate. Current cancer treatment modalities are still ineffective and associated with many side effects leading to robust research to find new specific target therapy. Heat shock factor (HSF)-1 is heat shock response mediator protein and act as transcription factor for HSP encoding gene. Many cancers have up-regulated HSP as a result of increase HSF-1 expression. Interestingly, inhibition of HSF-1 has no effect to normal cell, indicating HSF-1 as promises target therapy. RNAi is potential mechanism to block and down regulate HSF-1 which will affect many cellular processes in cancer cell. Combining RNAi base treatment with oncolityc viruses will boost the therapeutic effect of this novel treatment. Despite its potency, this modality still need further research in order to evaluate its efficacy and optimal doses to gain optimal result