Nuclear respiratory factor 1 promotes cell survival in multiple myeloma under proteasome inhibition therapy
Abstract
Abstract Multiple myeloma (MM) continues to be an incurable malignancy, even with recent therapeutic advancements. Although epigenetic dysregulation at cis-regulatory elements is known to drive disease progression, the complete molecular mechanisms underlying these alterations are poorly understood. Using Assay for Transposase-Accessible Chromatin with high-throughput sequencing analysis combined with the computational footprinting of CD138+ cells from 55 patients with MM, we depicted the dynamic changes in chromatin accessibility during disease progression and identified nuclear respiratory factor 1 (NRF1) as a master regulator of vital MM survival pathways. We demonstrated that NRF1 maintains proteasome homeostasis by orchestrating the ubiquitination pathway, which is essential for MM cell survival. We discovered a novel enhancer element that physically interacts with the NRF1 promoter, sustaining its expression. Targeting this enhancer RNA reduced NRF1 levels and increased tumor cell sensitivity to bortezomib (BTZ), suggesting therapeutic potential. In xenograft models, we showed that antisense oligonucleotides targeting the NRF1 enhancer, either alone or combined with BTZ, significantly decreased tumor burden and improved survival. Our findings reveal a previously unknown NRF1-dependent mechanism regulating MM cell survival and present a promising therapeutic approach through the manipulation of its regulatory network.
Article Details
Authors (24)
Tiziana Bruno
1Gene Expression and Cancer Models Unit, Department of Research and Advanced Technologies Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Maria Chiara Cappelletto
2Microbiology and Virology Unit, Clinic and Dermatology Research Department, San Gallicano Dermatological Institute IRCCS, Rome, Italy
Clelia Cortile
1Gene Expression and Cancer Models Unit, Department of Research and Advanced Technologies Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Stefano Di Giovenale
1Gene Expression and Cancer Models Unit, Department of Research and Advanced Technologies Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Bruno Amadio
1Gene Expression and Cancer Models Unit, Department of Research and Advanced Technologies Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Francesca De Nicola
1Gene Expression and Cancer Models Unit, Department of Research and Advanced Technologies Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Italia Falcone
1Gene Expression and Cancer Models Unit, Department of Research and Advanced Technologies Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Stefano Giuliani
Belinda Palermo
5Tumor Immunology and Immunotherapy Unit, Department of Research and Advanced Technologies Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Valeria Catena
1Gene Expression and Cancer Models Unit, Department of Research and Advanced Technologies Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Ludovica Ciuffreda
1Gene Expression and Cancer Models Unit, Department of Research and Advanced Technologies Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Fulvia Cerruti
6Department of Veterinary Sciences, University of Turin, Turin, Italy
Paolo Cascio
6Department of Veterinary Sciences, University of Turin, Turin, Italy
Roberta Merola
7Clinical Pathology Unit, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Serena Masi
7Clinical Pathology Unit, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Valentina De Pascale
8Translational Oncology Research Unit, Department of Research and Advanced Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Ombretta Annibali
Policlinico Universitario Campus Bio-Medico, Dipartimento di Medicina e Chirurgia Università Campus Bio-Medico, Rome
Silvia Ferraro
10Hematology Unit, Department of Hematology, St. Eugenio Hospital, Rome, Italy
Svitlana Gumenyuk
11Hematology and Stem Cell Transplant Unit, Clinical and Research Oncology Department, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Francesco Pisani
Laboratoire de Physique et d'′ Etude des Matériaux, LPEM, UMR 8213, ESPCI Paris, Université, PSL, CNRS, Sorbonne Université 2 , F-75005 Paris,
Francesco Marchesi
11Hematology and Stem Cell Transplant Unit, Clinical and Research Oncology Department, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Andrea Mengarelli
11Hematology and Stem Cell Transplant Unit, Clinical and Research Oncology Department, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Maurizio Fanciulli
Struttura di Area Funzionale di Ricerca Unit (SAFU), Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, Istituto di Ricovero e Cura a Carattere Scientifico Regina Elena National Cancer Institute
Giacomo Corleone
Struttura di Area Funzionale di Ricerca Unit (SAFU), Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, Istituto di Ricovero e Cura a Carattere Scientifico Regina Elena National Cancer Institute