A novel metadherin[DELTA]7 splice variant enhances triple negative breast cancer aggressiveness by modulating mitochondrial function via NFA¸B-SIRT3 axis

• Published in: Oncogene 2020-03, Vol.39 (10), p.2088
• Main Authors: Neeli, Praveen Kumar, Gollavilli, Paradesi Naidu, Mallappa, Sreevidya, Hari, Sai Gayathri, Kotamraju, Srigiridhar
• Format: Article
• Language: English
• Subjects: Breast cancer; Care and treatment; Cellular proteins; Development and progression; Gene expression; Genetic aspects; Health aspects
• ISSN: 0950-9232
• DOI: 10.1038/s41388-019-1126-6

Metadherin (MTDH) expression inversely correlates with prognosis of several cancers including mammary carcinomas. In this work, we identified a novel splice variant of MTDH with exon7 skipping (MTDH[DELTA]7) and its levels were found significantly high in triple negative breast cancer (TNBC) cells and in patients diagnosed with TNBC. Selective overexpression of MTDH[DELTA]7 in MDA-MB-231 and BT-549 cells enhanced proliferation, invasion, and epithelial-to-mesenchymal (EMT) transition markers in comparison to its wildtype counterpart. In contrast, knockdown of MTDH[DELTA]7 induced antiproliferative/antiinvasive effects. Mechanistically, MTDH-NFĸB-p65 complex activated SIRT3 transcription by binding to its promoter that in turn enhanced MnSOD levels and promoted EMT in TNBC cells. Intriguingly, mitochondrial OCR through Complex-I and -IV, and glycolytic rate (ECAR) were significantly high in MDA-MB-231 cells stably expressing MTDH[DELTA]7. While depletion of SIRT3 inhibited MTDH-Wt/[DELTA]7-induced OCR and ECAR, knockdown of MnSOD inhibited only ECAR. In addition, MTDH-Wt/[DELTA]7-mediated pro-proliferative/-invasive effects were greatly obviated with either siSIRT3 or siMnSOD in these cells. The functional relevance of MTDH[DELTA]7 was further proved under in vivo conditions in an orthotopic mouse model of breast cancer. Mice bearing labeled MDA-MB-231 cells stably expressing MTDH[DELTA]7 showed significantly more tumor growth and metastatic ability to various organs in comparison to MTDH-Wt bearing mice. Taken together, MTDH[DELTA]7 promotes TNBC aggressiveness through enhanced mitochondrial biogenesis/function, which perhaps serves as a biomarker.