2. Academic Validation
  3. BRD9 status is a major contributor for cysteine metabolic remodeling through MST and EAAT3 modulation in malignant melanoma

BRD9 status is a major contributor for cysteine metabolic remodeling through MST and EAAT3 modulation in malignant melanoma

  • Biochim Biophys Acta Mol Basis Dis. 2023 Dec 7:166983. doi: 10.1016/j.bbadis.2023.166983.
Ana Hipólito 1,  Renato Xavier 2,  Cheila Brito 2,  Ana Tomás 1,  Isabel Lemos 3,  Luís C Cabaço 4,  Fernanda Silva 1,  Abel Oliva 5,  Duarte C Barral 4,  João B Vicente 5,  Luís G Gonçalves 5,  Marta Pojo 2,  Jacinta Serpa 6
Affiliations

Affiliations

  • 1 iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056 Lisboa, Portugal; Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal.
  • 2 Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal.
  • 3 Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal; Instituto de Tecnologia Química e Tecnológica (ITQB) António Xavier da Universidade Nova de Lisboa, Av. da República, 2780-157 Oeiras, Portugal.
  • 4 iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056 Lisboa, Portugal.
  • 5 Instituto de Tecnologia Química e Tecnológica (ITQB) António Xavier da Universidade Nova de Lisboa, Av. da República, 2780-157 Oeiras, Portugal.
  • 6 iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056 Lisboa, Portugal; Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal. Electronic address: jacinta.serpa@fcm.unl.pt.
PMID: 38070581 DOI: 10.1016/j.bbadis.2023.166983
Abstract

Cutaneous melanoma (CM) is the most aggressive skin Cancer, showing globally increasing incidence. Hereditary CM accounts for a significant percentage (5-15 %) of all CM cases. However, most familial cases remain without a known genetic cause. Even though, BRD9 has been associated to CM as a susceptibility gene. The molecular events following BRD9 mutagenesis are still not completely understood. In this study, we disclosed BRD9 as a key regulator in cysteine metabolism and associated altered BRD9 to increased cell proliferation, migration and invasiveness, as well as to altered melanin levels, inducing higher susceptibility to melanomagenesis. It is evident that BRD9 WT and mutated BRD9 (c.183G>C) have a different impact on cysteine metabolism, respectively by inhibiting and activating MPST expression in the metastatic A375 cell line. The effect of the mutated BRD9 variant was more evident in A375 cells than in the less invasive WM115 line. Our data point out novel molecular and metabolic mechanisms dependent on BRD9 status that potentially account for the increased risk of developing CM and enhancing CM aggressiveness. Moreover, our findings emphasize the role of cysteine metabolism remodeling in melanoma progression and open new queues to follow to explore the role of BRD9 as a melanoma susceptibility or cancer-related gene.

Keywords

BRD9; Cutaneous melanoma; Cysteine metabolism; Metabolic remodeling.

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