Prostate cancer (PCa) is one of the most common cancers in men that usually develops slowly. Since diagnostic methods improved in the last decade and are highly precise, more cancers are diagnosed at an early stage. Active surveillance or watchful waiting are appealing approaches for men diagnosed with low-risk prostate cancer, and they are an antidote to the overtreatment problem and unnecessary biopsies. However, treatment depends on individual circumstances of a patient. Older hormonal therapies based on first generation antiandrogens and steroids were widely used in metastatic castration-resistant prostate cancer (mCRPC) patients prior to the implementation of docetaxel. Nowadays, accordingly to randomized clinical trials, abiraterone, enzalutamide, apalutamide. and docetaxel became first line agents administrated in the treatment of mCRPC. Furthermore, radium-223 is an optional therapy for bone-only metastasis patients. Sipuleucel-T demonstrated an overall survival benefit. However, other novel immunotherapeutics showed limitations in monotherapy. Possible combinations of new vaccines or immune checkpoint blockers with enzalutamide, abiraterone, radium-223, or docetaxel are the subject of ongoing rivalry regarding optimal therapy of prostate cancer.

Functional depletion of Muscleblind-like (MBNL) proteins is a key trigger of myotonic dystrophy (DM)-associated alternative splicing (AltS) defects. To overcome MBNL insufficiency in DM cell models, we harnessed a conserved endogenous mechanism of RNA activation (RNAa) via rationally designed small activating RNA (saRNA) targeted to the most active promoter of MBNL1 gene. We report on two lead saRNA duplexes that stimulated MBNL1 transcription via an on-site mechanism that involves AGO2-mediated loading of the antisense strand onto target sequence, followed by recruitment of RNAPII and auxiliary RNAa pathway components. We demonstrate that neither the antisense lncRNA MBNL1-AS1 overlapping MBNL1 promoter nor promoter-associated cryptic RNAs are mechanistically involved in saRNA-induced MBNL1 gene activation. Our data highlight putative transcription factors whose binding recruitment via identified saRNAs may affect MBNL1 expression. Most importantly, we show that RNAa-based approach upregulates MBNL1 protein content in distinct DM cell models and corrects the AltS of multiple MBNL1-regulated biomarker exons, underscoring the feasibility of adapting saRNA into novel therapeutic designs. This is the first report that site-specific augmentation of the endogenous MBNL1 transcription mitigates disease-associated AltS defects and as such, it offers new perspectives into therapeutic options against DM.

Cancer stem cells (CSCs) have been reported in various hematopoietic and solid tumors, therefore, are considered to promote cancer progression, metastasis, recurrence and drug resistance. However, regulation of CSCs at the molecular level is not fully understood. microRNAs (miRNAs) have been identified as key regulators of CSCs by modulating their major functions: self-renewal capacity, invasion, migration and proliferation. Various studies suggest that metformin, an anti-diabetic drug, has an anti-tumor activity but its precise mechanism of action has not been understood. The present article was written in accordance to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We systematically reviewed evidence for metformin’s ability to eradicate CSCs through modulating the expression of miRNAs in various solid tumors. PubMed and MEDLINE were searched from January 1990 to January 2020 for in vitro studies. Two authors independently selected and reviewed articles according to predefined eligibility criteria and assessed risk of bias of included studies. Four papers met the inclusion criteria and presented low risk bias. All of the included studies reported a suppression of CSCs’ major function after metformin dosage. Moreover, it was showed that metformin anti-tumor mechanism of action is based on regulation of miRNAs expression. Metformin inhibited cell survival, clonogenicity, wound-healing capacity, sphere formation and promotes chemosensitivity of tumor cells. Due to the small number of publications, aforementioned evidences are limited but may be consider as background for clinical studies.

The Muscleblind-like (MBNL) family comprises evolutionarily conserved RNA-binding proteins that interact with target RNAs via zinc finger domains. MBNLs orchestrate RNA processing, particularly alternative splicing, driving the developmental fetal-to-adult isoform switch across numerous target transcripts. This transition is a cornerstone in the process of MBNL-maintained cellular homeostasis and fails in many pathological conditions associated with deregulated expression or function of specific MBNL paralogs. This review provides current insights into the roles of MBNL genes and proteins in both health and disease. We examine their genomic architecture and protein organization and synthesize key insights from animal models to delineate the selective and compensatory functions of individual MBNL paralogs in physiology. To illustrate the roles of MBNLs in disease, we outline nucleotide repeat expansion disorders marked by their functional depletion, with a primary focus on myotonic dystrophy (DM). We also highlight selected cancer studies that have demonstrated the dual roles of MBNLs in tumorigenesis, encompassing both pro-oncogenic and tumor suppressive functions. Finally, using DM as a model, we review evidence for the therapeutic potential of endogenous MBNL gene modulation and argue that analogous strategies could be adapted and tailored to restore MBNL homeostasis in other disorders involving their dysregulation.