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MicroRNA-324-5p-CUEDC2 Axis Mediates Gain-of-Function Mutant p53-Driven Cancer Stemness.
Ghatak, Dishari; Datta, Arindam; Roychowdhury, Tanaya; Chattopadhyay, Samit; Roychoudhury, Susanta.
Afiliación
  • Ghatak D; Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India.
  • Datta A; Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India.
  • Roychowdhury T; Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India.
  • Chattopadhyay S; Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India.
  • Roychoudhury S; Department of Biological Sciences, BITS-Pilani, K K Birla Goa Campus, Goa, India.
Mol Cancer Res ; 19(10): 1635-1650, 2021 10.
Article en En | MEDLINE | ID: mdl-34257080
ABSTRACT
Regulation of cancer stemness has recently emerged as a new gain-of-function (GOF) property of mutant p53. In this study, we identify miR-324-5p as a critical epigenetic regulator of cancer stemness and demonstrate its role in mediating GOF-mutant p53-driven stemness phenotypes. We report that miR-324-5p is upregulated in human cancer cell lines and non-small cell lung carcinoma (NSCLC) tumors carrying TP53 GOF mutations. Mechanistically, we show that GOF mutant p53 upregulates miR-324-5p expression via c-Myc, an oncogenic transcription factor in cancer cells. Our experimental results suggest that miR-324-5p-induced CSC phenotypes stem from the downregulation of CUEDC2, a downstream target gene of miR-324-5p. Accordingly, CUEDC2 complementation diminishes elevated CSC marker expression in miR-324-5p-overexpressing cancer cells. We further demonstrate that mutant p53 cancer cells maintain a low level of CUEDC2 that is rescued upon miR-324-5p inhibition. Importantly, we identify CUEDC2 downregulation as a novel characteristic feature of TP53-mutated human cancers. We show that activation of NF-κB due to downregulation of CUEDC2 by miR-324-5p imparts stemness in GOF mutant p53 cancer cells. Finally, we provide evidence that TP53 mutations coupled with high miR-324-5p expression predict poor prognosis in patients with lung adenocarcinoma. Thus, our study delineates an altered miR-324-5p-CUEDC2-NF-κB pathway as a novel regulator of GOF mutant p53-driven cancer stemness. IMPLICATIONS Our findings implicate miRNA-324-5p as a novel epigenetic modifier of human cancer stemness.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Proteína p53 Supresora de Tumor / MicroARNs / Proteínas Adaptadoras Transductoras de Señales / Mutación con Ganancia de Función Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Mol Cancer Res Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2021 Tipo del documento: Article País de afiliación: India

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Proteína p53 Supresora de Tumor / MicroARNs / Proteínas Adaptadoras Transductoras de Señales / Mutación con Ganancia de Función Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Mol Cancer Res Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2021 Tipo del documento: Article País de afiliación: India