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Medizinische Klinik und Poliklinik III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
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Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
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ARMC5
is a tumor suppressor gene frequently mutated in primary bilateral macronodular adrenal hyperplasia (PBMAH), an adrenal cause of Cushing’s syndrome. The function of ARMC5 is poorly understood, aside from the fact that it regulates cell viability and adrenal steroidogenesis by mechanisms still unknown. Tumor suppressor genes play an important role in modifying intracellular redox response, which in turn regulates diverse cell signaling pathways. In this study, we demonstrated that inactivation in adrenocortical cells increased the expression of actors scavenging reactive oxygen species, such as superoxide dismutases (SOD) and peroxiredoxins (PRDX) by increasing the transcriptional regulator NRF1. Moreover, ARMC5 is involved in the NRF1 ubiquitination and in its half-life. Finally, inactivation alters adrenocortical steroidogenesis through the activation of p38 pathway and decreases cell sensitivity to ferroptosis participation to increase cell viability. Altogether, this study uncovers a function of ARMC5 as a regulator of redox homeostasis in adrenocortical cells, controlling steroidogenesis and cell survival.
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INSERM UMR745, Biological and Pharmaceutical Sciences University, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
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Department of Medical Oncology, Hôpital Cochin, Assistance Publique – Hôpitaux de Paris, Paris, France
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Department of Endocrinology, Cochin Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
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Department of Endocrinology, Cochin Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
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Department of Endocrinology, Cochin Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
Reference Center for Rare Adrenal Diseases, Reference Center for Rare Adrenal Cancer Network COMETE, Hôpital Cochin, AssistancePublique – Hôpitaux de Paris, Paris, France
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Department of Endocrinology, Cochin Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
Reference Center for Rare Adrenal Diseases, Reference Center for Rare Adrenal Cancer Network COMETE, Hôpital Cochin, AssistancePublique – Hôpitaux de Paris, Paris, France
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Search for other papers by Karine Perlemoine in
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Department of Endocrinology, APHP, Cochin Hospital, Paris, France
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ARMC5 (Armadillo repeat containing 5 gene) was identified as a new tumor suppressor gene responsible for hereditary adrenocortical tumors and meningiomas. ARMC5 is ubiquitously expressed and encodes a protein which contains a N-terminal Armadillo repeat domain and a C-terminal BTB (Bric-a-Brac, Tramtrack and Broad-complex) domain, both docking platforms for numerous proteins. At present, expression regulation and mechanisms of action of ARMC5 are almost unknown. In this study, we showed that ARMC5 interacts with CUL3 requiring its BTB domain. This interaction leads to ARMC5 ubiquitination and further degradation by the proteasome. ARMC5 alters cell cycle (G1/S phases and cyclin E accumulation) and this effect is blocked by CUL3. Moreover, missense mutants in the BTB domain of ARMC5, identified in patients with multiple adrenocortical tumors, are neither able to interact and be degraded by CUL3/proteasome nor alter cell cycle. These data show a new mechanism of regulation of the ARMC5 protein and open new perspectives in the understanding of its tumor suppressor activity.
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Department of Pathology, AP-HP, Hôpital Pitié-Salpétrière, Pierre et Marie Curie Université, Paris, France
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Department of Endocrinology, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France
Department of Hormonology, AP-HP, Hôpital Cochin, Paris, France
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Department of Hormonology, AP-HP, Hôpital Cochin, Paris, France
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Department of Endocrinology, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France
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Department of Endocrinology, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France
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Department of Endocrinology, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France
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Department of Endocrinology, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France
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Benign adrenal tumors cover a spectrum of lesions with distinct morphology and steroid secretion. Current classification is empirical. Beyond a few driver mutations, pathophysiology is not well understood. Here, a pangenomic characterization of benign adrenocortical tumors is proposed, aiming at unbiased classification and new pathophysiological insights. Benign adrenocortical tumors (n = 146) were analyzed by transcriptome, methylome, miRNome, chromosomal alterations and mutational status, using expression arrays, methylation arrays, miRNA sequencing, SNP arrays, and exome or targeted next-generation sequencing respectively. Pathological and hormonal data were collected for all tumors. Pangenomic analysis identifies four distinct molecular categories: (1) tumors responsible for overt Cushing, gathering distinct tumor types, sharing a common cAMP/PKA pathway activation by distinct mechanisms; (2) adenomas with mild autonomous cortisol excess and non-functioning adenomas, associated with beta-catenin mutations; (3) primary macronodular hyperplasia with ARMC5 mutations, showing an ovarian expression signature; (4) aldosterone-producing adrenocortical adenomas, apart from other benign tumors. Epigenetic alterations and steroidogenesis seem associated, including CpG island hypomethylation in tumors with no or mild cortisol secretion, miRNA patterns defining specific molecular groups, and direct regulation of steroidogenic enzyme expression by methylation. Chromosomal alterations and somatic mutations are subclonal, found in less than 2/3 of cells. New pathophysiological insights, including distinct molecular signatures supporting the difference between mild autonomous cortisol excess and overt Cushing, ARMC5 implication into the adreno-gonadal differentiation faith, and the subclonal nature of driver alterations in benign tumors, will orient future research. This first genomic classification provides a large amount of data as a starting point.
