Genome Biology | The team of Academician Song Weihong revealed the new mechanism of melanoma growth and progression

On October 30, the team of Weihong Song , Fellow of the Canadian Academy of Health Sciences (CAHS) and director of Oujiang Laboratory, worked together with the team of Professor Li Jun from the School of Basic Medical Sciences of Tianjin Medical University and the team of Professor Yang Jilong from Tianjin Medical University Cancer Institute & Hospital, published a breakthrough research of "Landscape of Enhancer Disruption and Functional Screen in Melanoma Cells" in Genome Biology (Zone 1 under the division of the Chinese Academy of Sciences, 5-Year IF = 17.4), a Top journal of genomics online. Oujiang Laboratory is the primary affiliation of this article.

Figure 1: Genome-wide identification and prioritization of highly recurrent regions (HRRs) based on 297 melanoma WGS data.

Melanoma, one of the most aggressive and malignant tumors, has a high fatality rate with over fifty thousand deaths reported each year worldwide. Previous large-scale genome sequencing studies have identified many putative cancer genes and hotspots in different types of melanomas. However, about 15% cutaneous melanoma and over 50% mucosal/acral melanoma patients are unclassified based on the pattern of the most prevalent significantly mutated genes, including BRAF, RAS, and NF1. Few studies have systematically characterized genomic events outside of protein-coding genes and their functions in melanoma development. The major challenge comes from the predominantly high mutation burden of the melanoma genome with a C>T nucleotide transition signature attributable to ultraviolet radiation. This hampers the identification of true melanoma drivers from background mutations by only relying on genome sequencing and computational modelling, especially in the non-coding genomic region. Therefore, the high mutation rate throughout the entire melanoma genome presents a major challenge in stratifying true driver events from the background mutations. Numerous recurrent non-coding alterations, such as those in enhancers, can shape tumor evolution, thereby emphasizing the importance in systematically deciphering enhancer disruptions in melanoma.

Figure 2: Functional screen of HRR-associated enhancers in melanoma.

The research teams developed algorithms and leveraged 297 melanoma whole-genome sequencing samples to prioritize highly recurrent regions. By performing a genome-scale CRISPR interference (CRISPRi) screen on highly recurrent region-associated enhancers in melanoma cells, the researchers identified 66 significant hits which could have tumor-suppressive roles. These functional enhancers show unique mutational patterns independent of classical significantly mutated genes in melanoma. Target gene analysis for the essential enhancers reveal many known and hidden mechanisms underlying melanoma growth. Utilizing extensive cell and animal experiments as well as melanoma clinical samples, the researchers demonstrated that a super enhancer element could modulate melanoma cell proliferation by targeting MEF2A, a new melanoma pathogenic gene, and another distal enhancer is able to sustain PTEN tumor-suppressive potential via long-range genome interactions. In conclusion, the study systematically establishes a catalogue of crucial enhancers and their target genes in melanoma growth and progression, and illuminates the identification of novel mechanisms of dysregulation for melanoma driver genes and new therapeutic targeting strategies. This study is of great significance for an in-depth understanding of melanoma growth and progression and their clinical treatment.

Figure 3: Long-range interactions between enhancer elements and tumor suppressor genes maintains melanoma-suppressive functions.

Dr. Wang Zhao, a postdoctoral fellow supervised by Academician Song Weihong of Oujiang Laboratory, Dr. Liang Qian of Wenzhou Medical University Scientific Research Center, Luo Menghan, a Master’s Student, and Zhao Ke, a doctoral student of Tianjin Medical University, are the co-first authors of this article. Academician  Weihong Song, Professor Li Jun, Professor Yang Jilong and Dr. Wang Zhao are the co-corresponding authors of this article. The work was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, the Tianjin Science and Technology Commission and the Oujiang Laboratory Director Fund project.

For the paper: https://genomebiology.biomedcentral.com/articles/10.1186/s13059-023-03087-5

Source: Wang Zhao

Editor: JEAN

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