RESUMO
Histone variants are emerging as key regulatory molecules in cancer. We report a unique role for the H2A.Z isoform H2A.Z.2 as a driver of malignant melanoma. H2A.Z.2 is highly expressed in metastatic melanoma, correlates with decreased patient survival, and is required for cellular proliferation. Our integrated genomic analyses reveal that H2A.Z.2 controls the transcriptional output of E2F target genes in melanoma cells. These genes are highly expressed and display a distinct signature of H2A.Z occupancy. We identify BRD2 as an H2A.Z-interacting protein, levels of which are also elevated in melanoma. We further demonstrate that H2A.Z.2-regulated genes are bound by BRD2 and E2F1 in an H2A.Z.2-dependent manner. Importantly, H2A.Z.2 deficiency sensitizes melanoma cells to chemotherapy and targeted therapies. Collectively, our findings implicate H2A.Z.2 as a mediator of cell proliferation and drug sensitivity in malignant melanoma, holding translational potential for novel therapeutic strategies.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Fator de Transcrição E2F1/genética , Histonas/genética , Melanoma/genética , Proteínas Serina-Treonina Quinases/genética , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/genética , Fator de Transcrição E2F1/metabolismo , Células HeLa , Histonas/biossíntese , Humanos , Melanócitos/citologia , Melanoma/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Pontos de Checagem da Fase S do Ciclo Celular/genética , Análise de Sequência de RNA , Fatores de Transcrição , Ativação TranscricionalRESUMO
A 73-year-old Hispanic woman presented to the clinic with an erythematous, friable 3.0 cm × 2.7 cm × 0.7 cm mass located on the posterior vertex of the scalp (Figure 1). The lesion had been present since birth but had recently begun to bleed intermittently, prompting evaluation. A biopsy was obtained, revealing a tumor with irregular, complex papillomatous invaginations lined by a two-layered epithelium. Atypical and crowded columnar cells lined the luminal aspect, while cuboidal cells lined the epithelium adjacent to the stroma (Figure 2). Decapitation secretion was noted in several areas on the luminal surface.
Assuntos
Carcinoma/patologia , Couro Cabeludo , Neoplasias das Glândulas Sudoríparas/patologia , Adenomas Tubulares de Glândulas Sudoríparas/patologia , Adulto , Carcinoma/cirurgia , Feminino , Humanos , Neoplasias das Glândulas Sudoríparas/cirurgia , Adenomas Tubulares de Glândulas Sudoríparas/cirurgiaRESUMO
A 28-year-old man of Middle-Eastern descent presented with a raised, pearly, slightly pigmented lesion on the right nasal ala. The lesion had been present for approximately 4 months. An excisional biopsy was taken, and the lesion measured 1.0 cm × 0.9 cm in dimension. The cut surface revealed a firm, white to tan nodule located within the dermis. The patient had no other significant medical history. After the initial excision, the lesion did not recur.