bims-ershed 2022-07-03 papers

Front Genet. 2022 ;13 911346

Unfolded Protein Response-Related Signature Associates With the Immune Microenvironment and Prognostic Prediction in Osteosarcoma.

Zhao Zhang, Xincheng Liu, Debin Cheng, Jingyi Dang, Zhenzhou Mi, Yubo Shi, Lei Wang, Hongbin Fan.

Background: Osteosarcoma is a highly malignant bone tumor commonly occurring in adolescents with a poor 5-year survival rate. The unfolded protein response (UPR) can alleviate the accumulation of misfolded proteins to maintain homeostasis under endoplasmic reticulum stress. The UPR is linked to the occurrence, progression, and drug resistance of tumors. However, the function of UPR-related genes (UPRRGs) in disease progression and prognosis of osteosarcoma remains unclear. Methods: The mRNA expression profiling and corresponding clinical features of osteosarcoma were acquired from TARGET and GEO databases. Consensus clustering was conducted to confirm different UPRRG subtypes. Subsequently, we evaluated the prognosis and immune status of the different subtypes. Functional analysis of GO, GSEA, and GSVA was used to reveal the molecular mechanism between the subtypes. Finally, four genes (STC2, PREB, TSPYL2, and ATP6V0D1) were screened to construct and validate a risk signature to predict the prognosis of patients with osteosarcoma. Result: We identified two subtypes according to the UPRRG expression patterns. The subgroup with higher immune scores, lower tumor purity, and active immune status was linked to a better prognosis. Meanwhile, functional enrichment revealed that immune-related signaling pathways varied markedly in the two subtypes, suggesting that the UPR might influence the prognosis of osteosarcoma via influencing the immune microenvironment. Moreover, prognostic signature and nomogram models were developed based on UPRRGs, and the results showed that our model has an excellent performance in predicting the prognosis of osteosarcoma. qPCR analysis was also conducted to verify the expression levels of the four genes. Conclusion: We revealed the crucial contribution of UPRRGs in the immune microenvironment and prognostic prediction of osteosarcoma patients and provided new insights for targeted therapy and prognostic assessment of the disease.

Keywords: immune infiltration; nomogram; osteosarcoma; prognostic prediction; unfolded protein response

DOI: https://doi.org/10.3389/fgene.2022.911346

Cell Death Discov. 2022 Jun 25. 8(1): 295

ATF6 prevents DNA damage and cell death in colon cancer cells undergoing ER stress.

Rossella Benedetti, Maria Anele Romeo, Andrea Arena, Maria Saveria Gilardini Montani, Livia Di Renzo, Gabriella D'Orazi, Mara Cirone.

Colon cancer represents one of the most common and aggressive cancers in its advanced state. Among the most innovative anti-cancer approaches, the manipulation of UPR is a promising one, effective also against cancers carrying dysfunctional p53. Interestingly, it is emerging that UPR cross-talks with DDR and that targeting the interplay between these two adaptive responses may be exploited to overcome the resistance to the single DDR- and UPR-targeting treatments. Previous studies have highlighted the role of IRE1 alpha and PERK UPR sensors on DDR, while the impact of ATF6 on this process remains under-investigated. This study shows for the first time that ATF6 sustains the expression level of BRCA-1 and protects colon cancer cells from the cytotoxic effect of ER stressors DPE and Thapsigargin. At molecular level, ATF6 activates mTOR to sustain the expression of HSP90, of which BRCA-1 is a client protein. Therefore, pharmacological or genetic inhibition of ATF6 promoted BRCA-1 degradation and increased DNA damage and cell death, particularly in combination with Adriamycin. All together this study suggests that targeting ATF6 may not only potentiate the cytotoxic effect of drugs triggering ER stress but may render colon cancer cells more sensitive to Adriamycin and possibly to other DNA damaging agents used to treat colon cancer.

DOI: https://doi.org/10.1038/s41420-022-01085-3

Comput Struct Biotechnol J. 2022 ;20 2871-2884

Secondary structures in RNA synthesis, splicing and translation.

Ilias Georgakopoulos-Soares, Guillermo E Parada, Martin Hemberg.

Even though the functional role of mRNA molecules is primarily decided by the nucleotide sequence, several properties are determined by secondary structure conformations. Examples of secondary structures include long range interactions, hairpins, R-loops and G-quadruplexes and they are formed through interactions of non-adjacent nucleotides. Here, we discuss advances in our understanding of how secondary structures can impact RNA synthesis, splicing, translation and mRNA half-life. During RNA synthesis, secondary structures determine RNA polymerase II (RNAPII) speed, thereby influencing splicing. Splicing is also determined by RNA binding proteins and their binding rates are modulated by secondary structures. For the initiation of translation, secondary structures can control the choice of translation start site. Here, we highlight the mechanisms by which secondary structures modulate these processes, discuss advances in technologies to detect and study them systematically, and consider the roles of RNA secondary structures in disease.

DOI: https://doi.org/10.1016/j.csbj.2022.05.041

Nat Commun. 2022 Jun 28. 13(1): 3722

Senescent cells limit p53 activity via multiple mechanisms to remain viable.

Ines Sturmlechner, Chance C Sine, Karthik B Jeganathan, Cheng Zhang, Raul O Fierro Velasco, Darren J Baker, Hu Li, Jan M van Deursen.

Super-enhancers regulate genes with important functions in processes that are cell type-specific or define cell identity. Mouse embryonic fibroblasts establish 40 senescence-associated super-enhancers regardless of how they become senescent, with 50 activated genes located in the vicinity of these enhancers. Here we show, through gene knockdown and analysis of three core biological properties of senescent cells that a relatively large number of senescence-associated super-enhancer-regulated genes promote survival of senescent mouse embryonic fibroblasts. Of these, Mdm2, Rnase4, and Ang act by suppressing p53-mediated apoptosis through various mechanisms that are also engaged in response to DNA damage. MDM2 and RNASE4 transcription is also elevated in human senescent fibroblasts to restrain p53 and promote survival. These insights identify key survival mechanisms of senescent cells and provide molecular entry points for the development of targeted therapeutics that eliminate senescent cells at sites of pathology.

DOI: https://doi.org/10.1038/s41467-022-31239-x