Melanoma is a high-grade malignant tumor of melanocytes, mostly occurring in melanocytes, and can also be seen in the extremities, mucous membranes and internal organs, accounting for about 3% of all tumors. In China, the acral type and mucosal type account for 418% and 226%。
Australia and New Zealand have the highest incidence of melanoma in the world, and the incidence of melanoma in Asian countries is significantly lower than that in Europe and the United States, but the incidence is increasing rapidly. The incidence of melanoma in our country is about 06 100,000 1 100,000 is significantly lower than that of Caucasians in Europe and the United States, but the annual growth rate of the incidence rate is 3% to 5%, which cannot be ignored. Although the overall incidence of melanoma in China is not high, the absolute number of melanoma cases in China has remained high due to the huge population base, with about 20,000 new cases every year.
*The melanoma genome has a C>T nucleotide conversion signature attributable to ultraviolet radiation, which prevents relying solely on genomic sequencing and computational models to identify true melanoma driver genes from background mutations, particularly in non-coding genomic regions. In these regions, many recurring non-coding changes, such as those in enhancers, can shape the evolution of tumors, thus emphasizing the importance of systematically resolving enhancer disruption in melanoma. Given the little knowledge of local hypermutation processes, establishing and elucidating the regulatory environment for melanoma, such as enhancer disruption, could provide an effective avenue for identifying non-coding drivers.
Recently, Tianjin Medical UniversityLi JunandYang JilongProfessorWenzhou Medical UniversitySong WeihongandDynastyProfessors communicate togethergenome biology**Published in:landscape of enhancer disruption and functional screen in melanoma cells66 significant points were identified that may have a tumor-inhibiting effect. Many of these enhancers attach distal targets or regulate uncharacterized melanoma driver genes based on the H3K27AC HiChip. The most significant enhancer, the E349 loop, is on the promoter of MEF2A, but not on its designed target gene IGF1R. MEF2A has different tumor suppressive or carcinogenic activities in different tumors. This studyThe key enhancer E 349 within a super-enhancer region was found to exert a tumor suppressive effect in melanoma by regulating the expression of MEF2A. In addition, there are several distal downstream enhancers that can maintain the tumor suppressor potential of PTEN in melanoma
In this study, the investigators systematically integrated 297 WGS datasets for melanoma and developed a strategy to estimate the HRR of SV and SNV indel. The researchers also devised a genome-scale CRISPRI screening method to study the function of HRR-related enhancers, found that some enhancers modulate genes that inhibit melanoma proliferation and survival through recurrent mutational tendencies, and found 66 enhancers that may exert growth inhibition in melanoma cells.
By applying H3K27AC HiChip chromatin loop detection, the researchers identified 200 target genes associated with functional HRR-associated enhancers. The integration of enhancer ligomes and CRISPRI screening identified several very important known or new cancer genes in melanoma carcinogenesis. An in-depth functional analysis showed thatWhen E 349 is deleted or extensively mutated, the expression of MEF2A is relatively low and the tumor proliferative ability is significantly stronger, and the loss of E 349 in melanoma can release tumor growth potential and promote BRAF inhibitor resistance;Under different conditions, the interaction frequency between the PTEN promoter and the core region of the E 156 enhancer was higher, which supported the regulatory relationship of the distal enhancer E 156 on melanoma PTEN, and inhibition of E 156 had a significant impact on the tumor survival phenotype, which highlighted the importance of the distal enhancer E 156 in maintaining the tumor suppressor potential of PTEN in melanoma cells.
In summary, this study established a catalog of key enhancers and their target genes in melanoma growth and progression, and elucidated a new mechanism and a new targeting strategy for melanoma driver gene dysregulation, laying a foundation for a comprehensive understanding and victory over melanoma. Research on acral melanoma is also underway.
Large-scale screening method and process of functional enhancers in melanoma. genome biology,2023,24:248.
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References
1. wang z, luo m, liang q, zhao k, hu y, wang w, feng x, hu b, teng j, you t, li r, bao z, pan w, yang t, zhang c, li t, dong x, yi x, liu b, zhao l, li m, chen k, song w, yang j, li mj.. landscape of enhancer disruption and functional screen in melanoma cells.genome biol
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