Disruption of the epigenetic program of gene expression is a hallmark of cancer that initiates and propagates tumorigenesis. Altered DNA methylation, histone modifications and ncRNAs expression are a feature of cancer cells. The dynamic epigenetic changes during oncogenic transformation are related to tumor heterogeneity, unlimited self-renewal and multi-lineage differentiation. This stem cell-like state or the aberrant reprogramming of cancer stem cells is the major challenge in treatment and drug resistance. Given the reversible nature of epigenetic modifications, the ability to restore the cancer epigenome through the inhibition of the epigenetic modifiers is a promising therapy for cancer treatment, either as a monotherapy or in combination with other anticancer therapies, including immunotherapies. Herein, we highlighted the main epigenetic alterations, their potential as a biomarker for early diagnosis and the epigenetic therapies approved for cancer treatment.

The imprinted H19 long non-coding RNA, a knowing oncofetal gene, presents a controversial role during the carcinogenesis process since its tumor suppressor or oncogenic activity is not completely elucidated. Since H19 lncRNA is involved in many biological pathways related to tumorigenesis, we sought to develop a non-cancer lineage with CRISPR-Cas9-mediated H19 knockdown (H19-) and observe the changes in a cellular context. To edit the promoter region of H19, two RNA guides were designed, and the murine C2C12 myoblast cells were transfected. H19 deletion was determined by DNA sequencing and gene expression by qPCR. We observed a small deletion (~ 60 bp) in the promoter region that presented four predicted transcription binding sites. The deletion reduced H19 expression (30%) and resulted in increased proliferative activity, altered morphological patterns including cell size and intracellular granularity, without changes in viability. The increased proliferation rate in the H19- cell seems to facilitate chromosomal abnormalities. The H19- myoblast presented characteristics similar to cancer cells, therefore the H19 lncRNA may be an important gene during the initiation of the tumorigenic process. Due to CRISPR/Cas9 permanent edition, the C2C12 H19- knockdown cells allows functional studies of H19 roles in tumorigenesis, prognosis, metastases, as well as drug resistance and targeted therapy.

A utilização de produtos naturais no desenvolvimento de novos fármacos tem sido amplamente discutida nos últimos 50 anos. Nesse sentido, a biodiversidade de diversos países influencia de maneira significativa na descoberta de novas moléculas bioativas, como os quimioterápicos de origem natural vimblastina e taxol. A bioprospecção, que se refere à coleta de novas espécies vegetais para serem testadas em modelos de screening e, posteriormente, em técnicas analíticas, gera diversas moléculas cujas atividades podem configurar potenciais ações biológicas no tratamento de diferentes enfermidades, como o câncer. Sob essa perspectiva, o presente trabalho tem como objetivo relacionar os modelos de screening, como o High Content Screening, o High Throughput Screening e a Triagem Virtual, na descoberta de novas moléculas. Além de analisar comparativamente instituições, legislações e os investimentos financeiros de diferentes países, no estudo e no desenvolvimento de novos compostos de origem naturais. Desse modo, foi possível concluir que, apesar de existirem esforços consideráveis para o aproveitamento da biodiversidade no avanço da ciência, estes ainda apresentam diversas dificuldades, principalmente no Brasil, o qual nunca estabeleceu um programa expressivo, em nível nacional ou contrato para implantar uma rede nacional de bioprospecção no país, conforme ocorreu em outras nações citadas.

No abstract

Prostate cancer is the second most common malignancy in men and the development of effective therapeutic strategies remains challenging when more advanced, androgen-independent or insensitive forms are involved. Accordingly, we have evaluated, using flow cytometry, confocal microscopy and image analysis, the antiproliferative effects of (+)-2,3,9-trimethoxypterocarpan [(+)-PTC, 1] on relevant human prostate cancer cells as well as its capacity to control mitosis within them. In particular, the studies reported herein reveal that (+)-PTC exerts anti-proliferative activity against the PC-3 cell lines by regulating cell-cycle progression with mitosis being arrested in the prophase or prometaphase. Furthermore, it emerges that treatment of the target cells with this compound results in the formation of monopolar spindles, disorganized centrosomes and extensively disrupted γ-tubulin distributions while centriole replication remains unaffected. Such effects suggest (+)-PTC should be considered as a possible therapy for androgen-insensitive/independent prostate cancer.