SUMMARY AMP-activated protein kinase (AMPK) is a master sensor and regulator of cellular energy status. Upon metabolic stress, AMPK suppresses anabolic and promotes catabolic processes to regain energy homeostasis. Cancer cells can occasionally suppress the growth restrictive AMPK pathway by mutation of an upstream regulatory kinase. Here, we describe a widespread mechanism to suppress AMPK through its ubiquitination and degradation by the cancer-specific MAGE-A3/6-TRIM28 ubiquitin ligase. MAGE-A3 and MAGE-A6 are highly similar proteins normally expressed only in the male germline, but frequently re-activated in human cancers. MAGE-A3/6 are necessary for cancer cell viability and sufficient to drive tumorigenic properties of non-cancerous cells. Screening for targets of MAGE-A3/6-TRIM28 revealed that it ubiquitinates and degrades AMPKα1. This leads to inhibition of autophagy, activation of mTOR signaling, and hypersensitization to AMPK agonists, such as metformin. These findings elucidate a germline mechanism commonly hijacked in cancer to suppress AMPK.

The Melanoma Antigen Gene (MAGE) protein family is a large, highly conserved group of proteins that share a common MAGE homology domain. Intriguingly, many MAGE proteins are restricted in expression to reproductive tissues, but are aberrantly expressed in a wide-variety of cancer types. Originally discovered as antigens on tumor cells and developed as cancer immunotherapy targets, recent literature suggests a more prominent role for MAGEs in driving tumorigenesis. This review will highlight recent developments into the function of MAGEs as oncogenes, their mechanisms of action in regulation of ubiquitin ligases, and outstanding questions in the field.

The cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) pathway functions to incorporate inorganic Fe-S cofactors into a variety of proteins, including several DNA repair enzymes. However, the mechanisms regulating the CIA pathway are unknown. We describe here that the MAGE-F1-NSE1 E3 ubiquitin ligase regulates the CIA pathway through ubiquitination and degradation of the CIA-targeting protein MMS19. Overexpression or knockout of MAGE-F1 altered Fe-S incorporation into MMS19-dependent DNA repair enzymes, DNA repair capacity, sensitivity to DNA-damaging agents, and iron homeostasis. Intriguingly, MAGE-F1 has undergone adaptive pseudogenization in select mammalian lineages. In contrast, MAGE-F1 is highly amplified in multiple human cancer types and amplified tumors have increased mutational burden. Thus, flux through the CIA pathway can be regulated by degradation of the substrate-specifying MMS19 protein and its downregulation is a common feature in cancer and is evolutionarily controlled.

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Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease of the lung with a characteristic feature of diffuse cystic changes in bilateral lungs. Lung transplantation is considered to be one of the effective treatments in end stage disease. Patients with LAM who underwent lung transplant tend to have more favorable outcome compared to other end stage lung diseases. We report a case of a female patient who was diagnosed with LAM and received bilateral lung transplantation at 45 years of age. Subsequent allograft biopsies were significant for mild acute cellular rejection (Grade A2), for which the immunosuppressive regimen was adjusted accordingly. At 7 years post-transplant, she presented with shortness of breath, cough, and fatigue, and diagnosed with a viral infection. Her chest imaging was unremarkable. However, a transbronchial biopsy was performed to rule out rejection and revealed foci of spindle cells proliferation, with positive HMB-45 and smooth muscle actin immunohistochemical studies, confirming the diagnosis of recurrent LAM. After she was discharged, she was re-admitted 1 week later with severe COVID-19. Her clinical course was complicated by acute respiratory distress syndrome, respiratory failure, and gastrointestinal hemorrhage. The patient passed away on day 36 of hospital stay. Autopsy was requested and confirmed the pathology of recurrent LAM and diffuse alveolar damage from COVID-19.