Dihydroartemisinin inhibits EMT of glioma via gene BASP1 in extrachromosomal DNA.

The mechanism of dihydroartemisinin (DHA) inhibiting the migration and invasion of glioma in an ROS-DSB-dependent manner has been revealed. Extrachromosomal DNAs (ecDNAs) which are generated by DNA damage have great potential in glioma treatment. However, the role of ecDNAs in DHA's pharmacological mechanisms in glioma is still unknown. In this study, DHA was found to inhibit proliferative activity, increase ROS levels and promote apoptosis in U87 and U251 cells. Migration and invasion have also been suppressed. ecDNA expression profiles were found in gliomas. EcDNA-BASP1 was found, by means of bioinformatics analysis, to be present in GBM tissues and positively correlated with patient prognosis. Proliferation, migration and invasion were upregulated after knockdown of ecDNA-BASP1. The expression of vimentin and N-cadherin also had the same tendency. Finally, we found that the ecDNA-BASP1 content in nude mouse transplant tumors was significantly increased after DHA treatment, which might exert a better suppressive effect on glioma. The upregulation of tumor suppressor ecDNA-BASP1 played an important role in the suppression of glioma progression induced by DHA. EcDNA-BASP1 may inhibit glioma migration and invasion through repressing epithelial-mesenchymal transition (EMT).

MGA-seq: robust identification of extrachromosomal DNA and genetic variants using multiple genetic abnormality sequencing.

Genomic abnormalities are strongly associated with cancer and infertility. In this study, we develop a simple and efficient method - multiple genetic abnormality sequencing (MGA-Seq) - to simultaneously detect structural variation, copy number variation, single-nucleotide polymorphism, homogeneously staining regions, and extrachromosomal DNA (ecDNA) from a single tube. MGA-Seq directly sequences proximity-ligated genomic fragments, yielding a dataset with concurrent genome three-dimensional and whole-genome sequencing information, enabling approximate localization of genomic structural variations and facilitating breakpoint identification. Additionally, by utilizing MGA-Seq, we map focal amplification and oncogene coamplification, thus facilitating the exploration of ecDNA's transcriptional regulatory function.

Pioneering insights of extrachromosomal DNA (ecDNA) generation, action and its implications for cancer therapy.

Extrachromosomal DNA (ecDNA) is a cancer-specific circular DNA molecule that is derived from chromosomes. In contrast with linear chromosomes, ecDNA exhibits a unique structure that can be representative of high chromosome accessibility, contributing to hyperactivated proto-oncogenes and malignant behaviours. Meanwhile, nonchromosomal inheritance and recurrent mutations of ecDNA fuel tumour heterogeneity and evolution. Recent studies have demonstrated that ecDNA drives tumorigenesis and progression and is related to poor clinical outcomes and drug resistance across widespread cancers. Although ecDNA was first observed in 1965, with technological advancements, its critical functions in tumorigenesis are currently coming forth. In this review, we summarize the current understanding of the origin, biogenesis process, discovery history, molecular mechanisms, and physiological functions of ecDNAs in cancer. Additionally, we highlight the effective research methods to study ecDNA and offer novel insights for ecDNA-directed therapies.

The biogenesis and roles of extrachromosomal oncogene involved in carcinogenesis and evolution.

More and more extrachromosomal DNA (ecDNA) was found in human tumor cells in recent years, which has a high copy number in tumors and changes the expression of oncogenes, thus different from normal chromosomal DNA. These circular structures were identified to originate from chromosomes, and play critical roles in rapid carcinogenesis, tumor evolution and multidrug resistance. Therefore, this review mostly focuses on the biogenesis and regulation of extrachromosomal oncogene in ecDNA as well as its function and mechanism in tumors, which are of great significance for our comprehensive understanding of the role of ecDNA in tumor carcinogenic mechanism and are expected to provide ecDNA with the potential to be a new molecular target for the diagnosis and treatment of tumors.

Origin of Extrachromosomal DNA and its Influence on Tumor Development / 中国生物化学与分子生物学报

Extrachromosomal DNA (ecDNA) is a class of circular DNA that is found off the chromosomes, either inside or outside the nucleus. ecDNA is abundant in cancer, and plays an important role during the tumor development. ecDNA contains multiple complete genes and regulatory elements that regulate transcription, including promoters and enhancers. It can replicate independently. However, the origin and mechanism of ecDNA is still unknown. Most scholars believe that DNA damage can elicit ecDNA production. The chromosomal fragments produced by DNA double-strand breaks are rearranged and circularized to form ecDNA via the non-homologous end-joining repair way. The chromatin on ecDNA is highly accessible and active. It works with oncogenes and co-amplify with enhancers to promote the transcription of oncogenes. Additionally, there are ultra-long-range chromatin contacts on ecDNA, which increases distant interaction. These features amplify the transcription of oncogenes and promote the development of tumors. Due to lack of centromeres, ecDNA has a non-equal segregation to daughter cells. Daughter cells, containing different copy numbers of ecDNA, can rapidly increase oncogene copy numbers, which drives the genome heterogeneity of the tumors. ecDNA-driven copy number regulation leads drug resistance and enables tumors to adapt quickly to the environment. Here we review the classification, origin of ecDNA and its role in tumorigenesis and development. We discuss the mechanisms of ecDNA promoting the transcription of oncogenes and leading to heterogeneity and drug resistance, aiming to provide new ideas on the diagnosis, treatment, and prognosis of tumors.