Super-enhancer-driven expression of BAHCC1 promotes melanoma cell proliferation and genome stability

Pietro Berico (1, 2) , Maguelone Nogaret (1) , Max Cigrang (1) , Antonin Lallement (1, 3) , Fatemeh Vand-Rajabpour (2, 4) , Amanda Flores-Yanke (1) , Giovanni Gambi (1) , Guillaume Davidson (1) , Leane Seno (1) , Jolian Obid (1) , Bujamin H. Vokshi (1) , Stéphanie Le Gras (1) , Gabrielle Mengus (1) , Tao Ye (1) , Carlos Fernandez Cordero (2) , Mélanie Dalmasso (5) , Emmanuel Compe (1) , Corine Bertolotto (5) , Eva Hernando (2) , Irwin Davidson (1) , Frédéric Coin (1)

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 NYU Grossman School of Medicine - New York University School of Medicine
3 IVH - Institut de Recherche sur les Maladies Virales et Hépatiques
4 NYU Langone Health [New York]
5 Biologie et pathologies des cellules mélanocytaires : de la pigmentation cutanée aux mélanomes

Super-enhancers (SEs) are stretches of enhancers ensuring a high level of expression of key genes associated with cell function. The identification of cancer-specific SE-driven genes is a powerful means for the development of innovative therapeutic strategies. Here, we identify a MITF/SOX10/TFIIH-dependent SE promoting the expression of BAHCC1 in a broad panel of melanoma cells. BAHCC1 is highly expressed in metastatic melanoma and is required for tumor engraftment, growth, and dissemination. Integrative genomics analyses reveal that BAHCC1 is a transcriptional regulator controlling expression of E2F/KLF-dependent cell-cycle and DNA-repair genes. BAHCC1 associates with BRG1-containing remodeling complexes at the promoters of these genes. BAHCC1 silencing leads to decreased cell proliferation and delayed DNA repair. Consequently, BAHCC1 deficiency cooperates with PARP inhibition to induce melanoma cell death. Our study identifies BAHCC1 as an SE-driven gene expressed in melanoma and demonstrates how its inhibition can be exploited as a therapeutic target.

Mots clés: Humans; Genomic Instability; gene expression; Cell Proliferation; Proteins; Melanoma; genome stability; Regulatory Sequences; Nucleic Acid; Cell Line; Tumor; Gene Expression Regulation; Neoplastic; Enhancer Elements; Genetic; BAHCC1; CP: Cancer; super-enhancer

Domaines: Cancer; Génomique, Transcriptomique et Protéomique [q-bio.GN]; Dermatologie

Pietro Berico, Maguelone Nogaret, Max Cigrang, Antonin Lallement, Fatemeh Vand-Rajabpour, et al.. Super-enhancer-driven expression of BAHCC1 promotes melanoma cell proliferation and genome stability. Cell Reports, 2023, 42 (11), pp.113363. ⟨10.1016/j.celrep.2023.113363⟩. ⟨hal-04398947⟩