Tumour microenvironment programming by an RNA-RNA-binding protein complex creates a druggable vulnerability in IDH-wild-type glioblastoma.

Patients with IDH-wild-type glioblastomas have a poor five-year survival rate along with limited treatment efficacy due to immune cell (glioma-associated microglia and macrophages) infiltration promoting tumour growth and resistance. To enhance therapeutic options, our study investigated the unique RNA-RNA-binding protein complex LOC-DHX15. This complex plays a crucial role in driving immune cell infiltration and tumour growth by establishing a feedback loop between cancer and immune cells, intensifying cancer aggressiveness. Targeting this complex with blood-brain barrier-permeable small molecules improved treatment efficacy, disrupting cell communication and impeding cancer cell survival and stem-like properties. Focusing on RNA-RNA-binding protein interactions emerges as a promising approach not only for glioblastomas without the IDH mutation but also for potential applications beyond cancer, offering new avenues for developing therapies that address intricate cellular relationships in the body.

STAMP2 suppresses autophagy in prostate cancer cells by modulating the integrated stress response pathway.

Six Transmembrane Protein of Prostate 2 (STAMP2) is critical for prostate cancer (PCa) growth. We previously showed that STAMP2 regulates the expression of stress induced transcription factor ATF4, which is implicated in starvation-induced autophagy. We therefore investigated whether STAMP2 is involved in the regulation of autophagy in PCa cells. Here we show that STAMP2 suppresses autophagy in PCa cells through modulation of the integrated stress response axis. We also find that STAMP2 regulates mitochondrial respiration. These findings suggest that STAMP2 has significant metabolic effects through mitochondrial function and autophagy, both of which support PCa growth.

NAIL: an evolutionarily conserved lncRNA essential for licensing coordinated activation of p38 and NFκB in colitis.

OBJECTIVE: NFκB is the key modulator in inflammatory disorders. However, the key regulators that activate, fine-tune or shut off NFκB activity in inflammatory conditions are poorly understood. In this study, we aim to investigate the roles that NFκB-specific long non-coding RNAs (lncRNAs) play in regulating inflammatory networks. DESIGN: Using the first genetic-screen to identify NFκB-specific lncRNAs, we performed RNA-seq from the p65-/- and Ikkß-/- mouse embryonic fibroblasts and report the identification of an evolutionary conserved lncRNA designated mNAIL (mice) or hNAIL (human). hNAIL is upregulated in human inflammatory disorders, including UC. We generated mNAILΔNFκB mice, wherein deletion of two NFκB sites in the proximal promoter of mNAIL abolishes its induction, to study its function in colitis. RESULTS: NAIL regulates inflammation via sequestering and inactivating Wip1, a known negative regulator of proinflammatory p38 kinase and NFκB subunit p65. Wip1 inactivation leads to coordinated activation of p38 and covalent modifications of NFκB, essential for its genome-wide occupancy on specific targets. NAIL enables an orchestrated response for p38 and NFκB coactivation that leads to differentiation of precursor cells into immature myeloid cells in bone marrow, recruitment of macrophages to inflamed area and expression of inflammatory genes in colitis. CONCLUSION: NAIL directly regulates initiation and progression of colitis and its expression is highly correlated with NFκB activity which makes it a perfect candidate to serve as a biomarker and a therapeutic target for IBD and other inflammation-associated diseases.

Noncoding RNAs: Master Regulators of Inflammatory Signaling.

Inflammatory signaling underlies many diseases, from arthritis to cancer. Our understanding of inflammation has thus far been limited to the world of proteins, because we are only just beginning to understand the role that noncoding RNAs (ncRNA) might play. It is now clear that ncRNA do not constitute transcriptional 'noise' but instead harbor physiological functions in controlling signaling pathways. In this review, we cover the newly discovered mechanisms and functions of ncRNAs in the regulation of inflammatory signaling. We also describe advances in experimental techniques allowing this field of research to take root. These findings have opened new avenues for putative therapeutic intervention in inflammatory diseases, which may be seen translated into clinical outcomes in the future.

Long-Range Chromatin Interactions Drive Mutant TERT Promoter Activation.

Cancer-specific TERT promoter mutations (-146C>T and -124C>T) have been linked to reactivation of the epigenetically silenced telomerase reverse transcriptase gene (TERT). Understanding how these single-nucleotide alterations drive TERT reactivation is a fundamental unanswered question and is key for making successful therapeutics. We show that unlike wild-type promoters, recruitment of the transcription factor GABPA specifically to mutant TERT promoters mediates long-range chromatin interaction and enrichment of active histone marks, and hence drives TERT transcription. CRISPR-mediated reversal of mutant TERT promoters, or deletion of its long-range interacting chromatin, abrogates GABPA binding and long-range interactions, leading to depletion of active histone marks, loss of POL2 recruitment, and suppression of TERT transcription. In contrast, de novo introduction of a TERT promoter mutation enables GABPA binding and upregulation of TERT via long-range interactions, acquisition of active histone marks, and subsequent POL2 recruitment. This study provides a unifying mechanistic insight into activation of mutant TERT promoters across various human cancers. SIGNIFICANCE: This study identifies a key mechanism by which cancer-specific mutant TERT promoters cause reactivation of TERT Because the mechanism uncovered here is not utilized by promoters that drive TERT in normal cells, this mechanism could be exploited to make inhibitors which have the potential to block telomerase function and hence the progression of up to 90% of human cancers. Cancer Discov; 6(11); 1276-91. ©2016 AACR.See related commentary by Min and Shay, p. 1212This article is highlighted in the In This Issue feature, p. 1197.

Reactivation of telomerase in cancer.

Activation of telomerase is a critical step in the development of about 85 % of human cancers. Levels of Tert, which encodes the reverse transcriptase subunit of telomerase, are limiting in normal somatic cells. Tert is subjected to transcriptional, post-transcriptional and epigenetic regulation, but the precise mechanism of how telomerase is re-activated in cancer cells is poorly understood. Reactivation of the Tert promoter involves multiple changes which evolve during cancer progression including mutations and chromosomal re-arrangements. Newly described non-coding mutations in the Tert promoter region of many cancer cells (19 %) in two key positions, C250T and C228T, have added another layer of complexity to telomerase reactivation. These mutations create novel consensus sequences for transcription factors which can enhance Tert expression. In this review, we will discuss gene structure and function of Tert and provide insights into the mechanisms of Tert reactivation in cancers, highlighting the contribution of recently identified Tert promoter mutations.