A metabolic prosurvival role for PML in breast cancer

Carracedo, Arkaitz; Weiss, Dror; Leliaert, Amy K.; Bhasin, Manoj; Boer, Vincent C.J. de; Laurent, Gaëlle; Adams, Andrew C.; Sundvall, Maria; Song, Su Jung; Ito, Keisuke; Finley, Lydia S.; Egia, Ainara; Libermann, Towia A.; Gerhart‐Hines, Zachary; Puigserver, Pere; Haigis, Marcia C.; Maratos-Flier, Elefteria; Richardson, Andrea L.; Schafer, Zachary T.; Pandolfi, Pier Paolo

doi:10.1172/jci62129

Cited by 238 publications

(316 citation statements)

References 80 publications

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“…Thus, IFN-initiated, PML-enforced hypersumoylation may control stem cell self-renewal and/or proliferation 42,55 . Lin28 controls metabolism 19,56 , as recently shown for PML 57,58 . Future studies should clarify any implication of SUMOs in these processes.…”

Section: Discussionmentioning

confidence: 55%

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

Şahin¹,

Ferhi²,

Carnec³

et al. 2014

Nat Commun

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Small ubiquitin-related modifier (SUMO) protein conjugation onto target proteins regulates multiple cellular functions, including defence against pathogens, stemness and senescence. SUMO1 peptides are limiting in quantity and are thus mainly conjugated to high-affinity targets. Conjugation of SUMO2/3 paralogues is primarily stress inducible and may initiate target degradation. Here we demonstrate that the expression of SUMO1/2/3 is dramatically enhanced by interferons through an miRNA-based mechanism involving the Lin28/let-7 axis, a master regulator of stemness. Normal haematopoietic progenitors indeed display much higher SUMO contents than their differentiated progeny. Critically, SUMOs contribute to the antiviral effects of interferons against HSV1 or HIV. Promyelocytic leukemia (PML) nuclear bodies are interferon-induced domains, which facilitate sumoylation of a subset of targets. Our findings thus identify an integrated interferon-responsive PML/SUMO pathway that impedes viral replication by enhancing SUMO conjugation and possibly also modifying the repertoire of targets. Interferon-enhanced post-translational modifications may be essential for senescence or stem cell self-renewal, and initiate SUMO-dependent proteolysis.

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Section: Discussionmentioning

confidence: 55%

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

Şahin¹,

Ferhi²,

Carnec³

et al. 2014

Nat Commun

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“…Adenosine 59-triphosphate (ATP) is the central cellular metabolic marker and bioenergetic source. 24,25 We observed a significant increase in basal intracellular ATP content in IL-7Ra 2 LSK HSCs purified from nonleukemic Fbxl10 Tg mice compared with the corresponding controls ( Figure 4D). These results strongly suggest that Fbxl10 metabolically activates HSCs by increasing OXPHOS, which is linked to the progression of cell cycle and promotes the development of leukemia.…”

Section: Org Frommentioning

confidence: 84%

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

Ueda¹,

Nagamachi

Takubo

et al. 2015

Blood

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• Fbxl10 is a bona fide oncogene in vivo. • Fbxl10 overexpression inHSCs induces mitochondrial metabolic activation and enhanced expression of Nsg2.We previously reported that deficiency for Samd9L, which was cloned as a candidate gene for 27/7q2 syndrome, accelerated leukemia cooperatively with enhanced expression of a histone demethylase: F-box and leucine-rich repeat protein 10 (Fbxl10, also known as Jhdm1b, Kdm2b, and Ndy1). To further investigate the role of Fbxl10 in leukemogenesis, we generated transgenic (Tg) mice that overexpress Fbxl10 in hematopoietic stem cells (HSCs). Interestingly, Fbxl10 Tg mice developed myeloid or B-lymphoid leukemia with complete penetrance. HSCs from the Tg mice exhibited an accelerated G0/G1-to-S transition with a normal G0 to G1 entry, resulting in pleiotropic progenitor cell expansion. Fbxl10 Tg HSCs displayed enhanced expression of neuron-specific gene family member 2 (Nsg2), and forced expression of Nsg2 in primary bone marrow cells resulted in expansion of immature cells. In addition, the genes involved in mitochondrial oxidative phosphorylation were markedly enriched in Fbxl10 Tg HSCs, coupled with increased cellular adenosine 59-triphosphate levels. Moreover, chromatin immunoprecipitation followed by sequencing analysis demonstrated that Fbxl10 directly binds to the regulatory regions of Nsg2 and oxidative phosphorylation genes. These findings define Fbxl10 as a bona fide oncogene, whose deregulated expression contributes to the development of leukemia involving metabolic proliferative advantage and Nsg2-mediated impaired differentiation. (Blood. 2015;125(22):3437-3446) IntroductionAppropriate patterns of epigenetic alterations in histone modifications are required to assure cell identity, and their deregulation can contribute to human diseases such as cancer. 1 We previously generated knockout mice for Samd9L (which was cloned as a candidate gene for the 27/7q2 syndrome frequently that is observed in myelodysplastic syndrome and acute leukemia patients) and demonstrated that mice deficient in Samd9L developed leukemia after a long latent period. 2 In addition, retroviral insertional mutagenesis revealed that the onset of the disease was highly accelerated with upregulation of F-box and leucine-rich repeat protein 10 (Fbxl10) or ectopic virus integration 1 (Evi1). 2 Clinically, an elevated expression of Fbxl10 is observed in patients with acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL), seminoma, and pancreatic ductal adenocarcinoma. [3][4][5][6] These findings prompted us to further investigate the role of Fbxl10 in leukemia development in vivo.Fbxl10 belongs to the JmjC domain-containing histone demethylases, and contains an N-terminal JmjC domain, followed by a CXXC zinc finger domain, a plant homeodomain finger, an F-box, and 8 leucine-rich repeats. 7 Fbxl10 preferentially demethylates the dimethylation of histone H3 at lysine 36 (H3K36me2), but not H3K36me1 and H3K36me3. 6,8 Fbxl10 was also recently reported to mediate the monoubiquitination of t...

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“…revised [38][39][40] . Here, we provide the first experimental demonstration for the tumorigenic potential of ATM activity, supporting the conclusion that ATM kinase, classically considered to be a tumour suppressor gene, may exert dual functions in cancer depending on the specific context.…”

Section: Discussionmentioning

confidence: 99%

ATM kinase sustains HER2 tumorigenicity in breast cancer

Stagni

Manni²,

Oropallo

et al. 2015

Nat Commun

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ATM kinase preserves genomic stability by acting as a tumour suppressor. However, its identification as a component of several signalling networks suggests a dualism for ATM in cancer. Here we report that ATM expression and activity promotes HER2-dependent tumorigenicity in vitro and in vivo. We reveal a correlation between ATM activation and the reduced time to recurrence in patients diagnosed with invasive HER2-positive breast cancer. Furthermore, we identify ATM as a novel modulator of HER2 protein stability that acts by promoting a complex of HER2 with the chaperone HSP90, therefore preventing HER2 ubiquitination and degradation. As a consequence, ATM sustains AKT activation downstream of HER2 and may modulate the response to therapeutic approaches, suggesting that the status of ATM activity may be informative for the treatment and prognosis of HER2-positive tumours. Our findings provide evidence for ATM's tumorigenic potential revising the canonical role of ATM as a pure tumour suppressor.

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A metabolic prosurvival role for PML in breast cancer

Cited by 238 publications

References 80 publications

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

ATM kinase sustains HER2 tumorigenicity in breast cancer

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