The m6A-independent role of epitranscriptomic factors in cancer.

Protein function alteration and protein mislocalization are cancer hallmarks that drive oncogenesis. N6-methyladenosine (m6A) deposition mediated by METTL3, METTL16, and METTL5 together with the contribution of additional subunits of the m6A system, has shown a dramatic impact on cancer development. However, the cellular localization of m6A proteins inside tumor cells has been little studied so far. Interestingly, recent evidence indicates that m6A methyltransferases are not always confined to the nucleus, suggesting that epitranscriptomic factors may also have multiple oncogenic roles beyond m6A that still represent an unexplored field. To date novel epigenetic drugs targeting m6A modifiers, such as METTL3 inhibitors, are entering into clinical trials, therefore, the study of the potential onco-properties of m6A effectors beyond m6A is required. Here we will provide an overview of methylation-independent functions of the m6A players in cancer, describing the molecular mechanisms involved and the future implications for therapeutics.

Interplay between m6 A epitranscriptome and epigenome in cancer: current knowledge and therapeutic perspectives.

Chromatin has an extremely flexible structure that allows the fine regulation of gene expression. To orchestrate this process, small chemical modifications are dynamically added or removed on DNA, RNA and histone substrates. Epigenetic modifications govern a plethora of key cellular functions, whose dysregulation contributes to oncogenesis. The interrelationship between (irreversible) genetic mutations and (reversible) epigenetic alterations and how this crosstalk regulates gene expression has long been a major area of interest. Marks modulating the RNA code (epitranscriptome), such as the well-studied N6 -methyladenosine (m6 A), are known to influence stability, metabolism and life cycle of many mRNAs, including cancer-associated transcripts. Together, epigenetic and epitranscriptomic pathways therefore control the entire cellular expression profile and, eventually, cell fate. Recently, previously undescribed crosstalk between these two pathways has started to be unrevealed. For example, m6 A and its effectors cooperate with histone modifications to localize chromatin-modifying complexes to their target regions. Epigenetic marks governing the expression of m6 A factors can also be found at specific genetic loci. m6 A itself can mark noncoding RNAs (including lncRNAs, circRNAs and miRNAs), influencing their structure, maturation and function. These interactions affect both cell physiology and pathology. Clear evidence that dysregulation of this network plays a role in cancer has emerged, suggesting a new layer of complexity in the landscape of gene expression. Here, we summarize current knowledge on the interplay between m6 A epitranscriptome and epigenome, focusing on cancer processes. We also discuss strategies to target m6 A machinery for future therapeutic intervention.

Socio-economic determinants of subjective wellbeing toward Sustainable Development Goals: An insight from a developing country.

One of the goals of happiness research is to identify the key factors that influence it. Therefore, the present research is designed to examine the determining factors of subjective wellbeing (SWB) in Pakistan. The present research is conducted by collecting the data of 1,566 households in Punjab, Pakistan, using the ordered logit and tobit model. The findings of this research confirm that income, education, government effectiveness, no perceived corruption, and perceived institutional quality improve wellbeing, while lower trust in family and friends, poor health status, living on rent, and dissatisfaction with the services of hospitals lower the level of wellbeing. But individuals with more social ties, who face barriers in health services, live more happily satisfied with their lives. Crime victimization and worrisome terrorism also lower the level of SWB. Findings of research strongly emphasize policymakers and government institutions to improve their quality and take essential measures for improving the governance structure.

Cucurbitacin E Triggers Cellular Senescence in Colon Cancer Cells via Regulating the miR-371b-5p/TFAP4 Signaling Pathway.

The induction of cellular senescence is considered as a potent strategy to suppress cancer progression. Cucurbitacin E (CE) belongs to the triterpenoids and has received substantial attention for its antineoplastic property. However, the function of CE on cellular senescence remained elusive. Herein, we revealed that CE significantly induced cellular senescence in colorectal cancer (CRC) cells. The CE effects on the cellular senescence in CRC cells were confirmed by observing the common features of the senescence, such as the enhanced activity of senescence-associated ß-galactosidase, γ-H2AX positive staining, and upregulation of senescence-associated proteins including p53, p27, and p21. Moreover, CE exerted pro-senescent effects in CRC cells via attenuating the transcription factor activating enhancer-binding protein 4 (TFAP4) expression, and the ectopic expression of TFAP4 blocked the CE-induced senescence. Mechanistically, CE treatment caused a robust increase in miR-371b-5p, which markedly repressed TFAP4. In contrast, silencing of miR-371b-5p counteracted the percentages of CE-induced senescent cells from 37.49 ± 2.61 to 7.06 ± 0.91% in HCT-116 cells via derepressing TFAP4 to attenuate the expression of p53, p21, and p16. Altogether, these results demonstrated that dietary CE induces CRC cellular senescence via modulating the miR-371b-5p/TFAP4 axis and presents opportunities for potential therapeutic strategies against CRC.

Cucurbitacin E Chemosensitizes Colorectal Cancer Cells via Mitigating TFAP4/Wnt/ß-Catenin Signaling.

Chemoresistance and toxicity are the main obstacles that limit the efficacy of 5-fluorouracil (5-FU) in colorectal cancer (CRC) therapy. Hence, it is urgent to identify new adjuvants that can sensitize CRC cells to conventional chemotherapeutic approaches. Cucurbitacin E (CE) is a natural triterpenoid, widely distributed in dietary plants, and shows antitumor effects. Here, we report that CE enhances the sensitivity of CRC cells to chemotherapy via attenuating the expression of adenosine 5'-triphosphate (ATP)-binding cassette transporters ABCC1 and MDR1. Combined with CE-functionalized magnetite nanoparticles and gene ontology analysis, we found that CE-binding proteins may involve Wnt/ß-catenin signaling. To validate the findings, ß-catenin was upregulated in drug-resistant cell lines, and the synergistic effects of CE and chemotherapeutics were accompanied by the downregulation of ß-catenin. Moreover, TFAP4 was identified as an intracellular target of CE. Remarkably, the combination of CE and 5-FU treatment attenuated ß-catenin, MDR1, and ABCC1 expressions, while TFAP4 overexpression reversed their expressions by 2.68 ± 0.46-, 0.72 ± 0.44-, and 0.93 ± 0.21-fold, respectively. Thus, our results indicate that CE sensitizes CRC cells to chemotherapy by decreasing the TFAP4/Wnt/ß-catenin signaling, suggesting that the dietary compound CE can be used as a chemosensitizing adjuvant for CRC treatment.

A novel miR-206/hnRNPA1/PKM2 axis reshapes the Warburg effect to suppress colon cancer growth.

Alternative splicing of pyruvate kinase gene (PKM) results in a higher PKM2/PKM1 ratio that contributes to the Warburg effect and reversing the Warburg effect has opened novel avenues for cancer treatment. miR-206 functions as a tumor suppressor in several types of cancer. However, the effect and underlying mechanisms of miR-206 on the Warburg effect are not yet elucidated. Here, we showed that miR-206 expression was obviously decreased in CRC tissues based on LinkedOmics. A significant decrease in miR-206 expression was negatively correlated with advanced tumor stage, while inversely correlated with overall survival in CRC patients. Ectopic overexpression of miR-206 has dramatically restricted the cell proliferation, glucose consumption and lactate production in CRC cells, whereas transfection of miR-206 inhibitor exhibited the opposite results. Furthermore, miR-206 overexpression induced switching from PKM2 to PKM1 via modulating alternative splicing of PKM gene. The alternative splicing factor hnRNPA1 is identified as the direct functional target of miR-206. Mechanistically, miR-206 overexpression directly targeted hnRNPA1 to suppress PKM2 expression to attenuate Warburg effect and cell proliferation of CRC. Importantly, the restoration of hnRNPA1 expression mostly abrogated the miR-206-meditated Warburg effect. Collectively, these results revealed that the novel miR-206/hnRNPA1/PKM2 axis plays a pivotal role in the Warburg effect to modulate CRC progression.

Avenanthramide A triggers potent ROS-mediated anti-tumor effects in colorectal cancer by directly targeting DDX3.

Colorectal cancer (CRC) is a common malignant gastrointestinal tumor with high mortality worldwide. Drug resistance and cytotoxicity to normal cells are the main causes of chemotherapeutic treatment failure in CRC. Therefore, extracting the bioactive compounds from natural products with anti-carcinogenic activity and minimal side-effects is a promising strategy against CRC. The present study aims to evaluate the anti-carcinogenic properties of avenanthramides (AVNs) extracted from oats bran and clarify the underlying molecular mechanisms. We demonstrated that AVNs treatment suppressed mitochondrial bioenergetic generation, resulting in mitochondrial swelling and increased reactive oxygen species (ROS) production. Further study indicated that AVNs treatment significantly reduced DDX3 expression, an oncogenic RNA helicase highly expressed in human CRC tissues. DDX3 overexpression reversed the ROS-mediated CRC apoptosis induced by AVNs. Of note, we identified Avenanthramide A (AVN A) as the effective ingredient in AVNs extracts. AVN A blocked the ATPase activity of DDX3 and induced its degradation by directly binding to the Arg287 and Arg294 residues in DDX3. In conclusion, these innovative findings highlight that AVNs extracts, in particular its bioactive compound AVN A may crack the current hurdles in the way of CRC treatment.

The potential immunotoxicity of fine particulate matter based on SD rat spleen.

Health risks have been closely related to increased exposure of fine particulate matter (PM2.5) in general population. Immune system is considered to be a most vulnerable target for airborne pollutants. PM2.5 could make some serious damages to the body organs by inducing immunotoxicity. However, the underlying molecular mechanisms are still unclear. The purpose of this study is aimed to elucidate the possible mechanisms of PM2.5-mediated immunotoxicity on spleen organ by using SD rat models. This research demonstrated that the spleen structure damage induced by PM2.5 treatment was more pronounced in winter than in summer. Mechanistically, TUNEL staining show a considerable increase in spleen apoptosis by summer and winter PM2.5 exposures compared with control. However, winter PM2.5 exposure caused more toxicity in the spleen than summer PM2.5 exposure. Furthermore, our results illustrated that PM2.5 triggered oxidative stress and ERS in spleen tissues of SD rats, and lead to apoptosis via upregulation of CHOP and caspase-12. Likewise, the protein levels of LC3 were significantly increased and p62 was decreased by PM2.5 exposure, thereby activated the autophagy of spleen in SD rats in a concentration-dependent manner. In conclusion, this study supported that PM2.5 mediated the immunotoxicity by the occurrence of stimulation of ERS and autophagy in SD rats. Taken together, these findings suggest PM2.5 as potential agent of immunotoxicity that needs an urgent attention. Graphical abstract Graphical abstract contains poor quality of text inside the artwork. Please do not re-use the file that we have rejected or attempt to increase its resolution and re-save. It is originally poor, therefore, increasing the resolution will not solve the quality problem. We suggest that you provide us the original format. We prefer replacement figures containing vector/editable objects rather than embedded images. Preferred file formats are eps, ai, tiff and pdf.Thanks you attention. We will provide tiff format image.

Pyruvate kinase M2: A multifarious enzyme in non-canonical localization to promote cancer progression.

Rewiring glucose metabolism, termed as Warburg effect or aerobic glycolysis, is a common signature of cancer cells to meet their high energetic and biosynthetic demands of rapid growth and proliferation. Pyruvate kinase M2 isoform (PKM2) is a key player in such metabolic reshuffle, which functions as a rate-limiting glycolytic enzyme in the cytosol of highly-proliferative cancer cells. During the recent decades, PKM2 has been extensively studied in non-canonical localizations such as nucleus, mitochondria, and extracellular secretion, and pertained to novel biological functions in tumor progression. Such functions of PKM2 open a new avenue for cancer researchers. This review summarizes up-to-date functions of PKM2 at various subcellular localizations of cancer cells and draws attention to the translocation of PKM2 from cytosol into the nucleus induced by posttranslational modifications. Moreover, PKM2 in tumor cells could have an important role in resistance acquisition processes against various chemotherapeutic drugs, which have raised a concern on PKM2 as a potential therapeutic target. Finally, we summarize the current status and future perspectives to improve the potential of PKM2 as a therapeutic target for the development of anticancer therapeutic strategies.