RESUMO
Mutations of the tricarboxylic acid cycle enzyme fumarate hydratase cause hereditary leiomyomatosis and renal cell cancer. Fumarate hydratase-deficient renal cancers are highly aggressive and metastasize even when small, leading to a very poor clinical outcome. Fumarate, a small molecule metabolite that accumulates in fumarate hydratase-deficient cells, plays a key role in cell transformation, making it a bona fide oncometabolite. Fumarate has been shown to inhibit α-ketoglutarate-dependent dioxygenases that are involved in DNA and histone demethylation. However, the link between fumarate accumulation, epigenetic changes, and tumorigenesis is unclear. Here we show that loss of fumarate hydratase and the subsequent accumulation of fumarate in mouse and human cells elicits an epithelial-to-mesenchymal-transition (EMT), a phenotypic switch associated with cancer initiation, invasion, and metastasis. We demonstrate that fumarate inhibits Tet-mediated demethylation of a regulatory region of the antimetastatic miRNA cluster mir-200ba429, leading to the expression of EMT-related transcription factors and enhanced migratory properties. These epigenetic and phenotypic changes are recapitulated by the incubation of fumarate hydratase-proficient cells with cell-permeable fumarate. Loss of fumarate hydratase is associated with suppression of miR-200 and the EMT signature in renal cancer and is associated with poor clinical outcome. These results imply that loss of fumarate hydratase and fumarate accumulation contribute to the aggressive features of fumarate hydratase-deficient tumours.
Assuntos
Epigênese Genética , Transição Epitelial-Mesenquimal , Fumaratos/metabolismo , Animais , Movimento Celular , Células Cultivadas , Fumarato Hidratase/deficiência , Fumarato Hidratase/genética , Fumarato Hidratase/metabolismo , Células HEK293 , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Mesoderma/metabolismo , Camundongos , MicroRNAs/genética , Fatores de Transcrição/metabolismo , TranscriptomaRESUMO
Se presenta una paciente de 58 años que consulta por traumatismo en mama derecha. Se observa una equimosis en piel de la mama derecha con una induración subyacente poco definida. La ecografía mostró características de un hematoma en organización. La mamografía informó la presencia de un nódulo irregular. La biopsia por congelación fue positiva para carcinoma infiltrante. Se realiza cirugía con mastectomía radical modificada. La anatomía patológica informa carcinoma mioepitelioma variedad células fusiformes. Hasta la fecha, la paciente se encuentra libre de enfermedad locoregional y a distancia.
A 58 year old female patient presenting a trauma in her right breast visits the hospital. A skin ecchymosis on the right breast with a not well defined underlying induration is observed. The sonogram shows the characteristics typical of forming ecchymoses. The mammogram reports the presence of an irregular lump. Cold biopsy is positive for infiltrating carcinoma. A radical modified mastectomy is performed. Pathological anatomy reports that it is a myoepithelioma, carcinoma, fusiform cell variety. Up to the present, the patient is free from local-regional and remote disease.
