CD74-AKT Axis Is a Potential Therapeutic Target in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) cells are often resistant to FAS (CD95)-mediated apoptosis, but the underlying molecular mechanism(s) is not fully understood yet. Notably, the expression of the type II transmembrane protein, CD74, is correlated with chemotherapy-resistant and more invasive forms of cancers via unknown mechanisms. Here, we analyzed gene expression pattern of cancer patients and/or patient-derived xenograft (PDX) models and found that mRNA and protein levels of CD74 are highly expressed in TNBC and correlated with cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) properties. Mechanistically, we found that AKT activation is likely critical for maintaining CD74 expression and protein stability to favor its oncogenic functions. Physiologically, epidermal growth factor (EGF) along with CD74 could activate AKT signaling, likely through binding of phosphorylated AKT (S473) to CD74, whereas inhibition of AKT could impair stability of CD74. We also revealed that CD74 binds to FAS and interferes with the intrinsic signaling of FAS-mediated apoptosis. As such, selective targeting of the CD74/FAS complex using the AKT inhibitor along with the CD74-derived peptide could synergistically restore and activate FAS-mediated apoptosis. Therefore, our approach of mobilizing apoptosis pathways likely provides a rationale for TNBC treatment by targeting the CD74/FAS and CD74-AKT axes.

Pharmacological inhibition of the SKP2/p300 signaling axis restricts castration-resistant prostate cancer.

SKP2, an F-box protein of the SCF type of the E3 ubiquitin ligase complex, plays an important function in driving tumorigenesis through the destruction of numerous tumor-suppressive proteins. Besides its critical role in cell cycle regulation, proto-oncogenic functions of SKP2 have also been shown in a cell cycle regulation-independent manner. Therefore, uncovering novel physiological upstream regulators of SKP2 signaling pathways would be essential to retard aggressive malignancies. Here, we report that elevation of SKP2 and EP300 transcriptomic expression is a hallmark of castration-resistant prostate cancer. We also found that SKP2 acetylation is likely a critical driven event in castration-resistant prostate cancer cells. Mechanistically, SKP2-acetylation is mediated by the p300 acetyltransferase enzyme for post-translational modification (PTM) event that is induced upon stimulation with dihydrotestosterone (DHT) in prostate cancer cells. Moreover, ectopic expression of acetylation-mimetic K68/71Q mutant of SKP2 in LNCaP cells could confer resistance to androgen withdrawal-induced growth arrest and promotes prostate cancer stem cell (CSC)-like traits including survival, proliferation, stemness formation, lactate production, migration, and invasion. Furthermore, inhibition of p300-mediated SKP2 acetylation or SKP2-mediated p27-degradation by pharmacological inhibition of p300 or SKP2 could attenuate epithelial-mesenchymal transition (EMT) and the proto-oncogenic activities of the SKP2/p300 and androgen receptor (AR) signaling pathways. Therefore, our study identifies the SKP2/p300 axis as a possible molecular mechanism driving castration-resistant prostate cancers, which provides pharmaceutical insight into inactivation of the SKP2/p300 axis for restriction of CSC-like properties, thereby benefiting clinical diagnosis and cancer therapy.

CAR T-Cell Therapy for Patients with Multiple Myeloma: Current Evidence and Challenges.

The therapeutic landscape of multiple myeloma (MM) has benefited from an emergence of novel therapies over the last decade. By inducing T-cell kill of target cancer cells, chimeric antigen receptor (CAR) T-cell therapies have improved outcomes of patients with hematologic malignancies. B-cell maturation antigen (BCMA) is the current target antigen of choice for most CAR T-cell products under investigation for MM. However, their shortcomings deal with logistical and clinical challenges, including limited availability, manufacturing times, and toxicities. This article provides an overview of recently developed and investigational CAR T-cell therapies for MM, highlighting current evidence and challenges.

Neural and self-report indices of cognitive reappraisal moderate the association between sensitivity to uncertain threat and problem alcohol use.

Exaggerated reactivity to threats that are uncertain (U-threat) is a risk factor for problem alcohol use. Data suggest that exaggerated reactivity to U-threat is associated with chronic anxiety and motivation for coping-oriented drinking. Not all individuals with high U-threat reactivity engage in excessive drinking and theory and research suggest that individual differences in emotion regulation, particularly frequency and effectiveness of cognitive reappraisal, are potential moderators of this well-established link. The aim of the current study was to test this hypothesis using a multimodal laboratory design. A total of 83 volunteers with depression and/or anxiety completed a well-validated threat sensitivity task and two complimentary assessments of cognitive reappraisal. Threat sensitivity was measured using startle eyeblink potentiation during threat-of-electric shock. Cognitive reappraisal was measured using self-report and estimates of prefrontal cortex activation (PFC; i.e., ventrolateral, dorsolateral and dorsomedial) during instructed reappraisal during functional magnetic resonance imaging. Results revealed self-reported and PFC indices of reappraisal were correlated within-subjects. Additionally, self-reported and ventrolateral (vlPFC) activation during reappraisal moderated the association between reactivity to U-threat and problem alcohol use. Across both measures, at low engagement in reappraisal, greater startle reactivity to U-threat was associated with greater problem alcohol use. At high engagement in reappraisal, there was no association between U-threat reactivity and problem alcohol use. Together, the findings reveal that exaggerated reactivity to U-threat may be a particularly robust risk factor for problem alcohol use in the context of impaired or ineffective emotion regulation.

ATM: Main Features, Signaling Pathways, and Its Diverse Roles in DNA Damage Response, Tumor Suppression, and Cancer Development.

ATM is among of the most critical initiators and coordinators of the DNA-damage response. ATM canonical and non-canonical signaling pathways involve hundreds of downstream targets that control many important cellular processes such as DNA damage repair, apoptosis, cell cycle arrest, metabolism, proliferation, oxidative sensing, among others. Of note, ATM is often considered a major tumor suppressor because of its ability to induce apoptosis and cell cycle arrest. However, in some advanced stage tumor cells, ATM signaling is increased and confers remarkable advantages for cancer cell survival, resistance to radiation and chemotherapy, biosynthesis, proliferation, and metastasis. This review focuses on addressing major characteristics, signaling pathways and especially the diverse roles of ATM in cellular homeostasis and cancer development.

Impact of diabetes on promoting the growth of breast cancer.

BACKGROUND: Type II diabetes mellitus (DM2) is a significant risk factor for cancers, including breast cancer. However, a proper diabetic breast cancer mouse model is not well-established for treatment strategy design. Additionally, the precise diabetic signaling pathways that regulate cancer growth remain unresolved. In the present study, we established a suitable mouse model and demonstrated the pathogenic role of diabetes on breast cancer progression. METHODS: We successfully generated a transgenic mouse model of human epidermal growth factor receptor 2 positive (Her2+ or ERBB2) breast cancer with DM2 by crossing leptin receptor mutant (Leprdb/+ ) mice with MMTV-ErbB2/neu) mice. The mouse models were administrated with antidiabetic drugs to assess the impacts of controlling DM2 in affecting tumor growth. Magnetic resonance spectroscopic imaging was employed to analyze the tumor metabolism. RESULTS: Treatment with metformin/rosiglitazone in MMTV-ErbB2/Leprdb/db mouse model reduced serum insulin levels, prolonged overall survival, decreased cumulative tumor incidence, and inhibited tumor progression. Anti-insulin resistance medications also inhibited glycolytic metabolism in tumors in vivo as indicated by the reduced metabolic flux of hyperpolarized 13 C pyruvate-to-lactate reaction. The tumor cells from MMTV-ErbB2/Leprdb/db transgenic mice treated with metformin had reprogrammed metabolism by reducing levels of both oxygen consumption and lactate production. Metformin decreased the expression of Myc and pyruvate kinase isozyme 2 (PKM2), leading to metabolism reprogramming. Moreover, metformin attenuated the mTOR/AKT signaling pathway and altered adipokine profiles. CONCLUSIONS: MMTV-ErbB2/Leprdb/db mouse model was able to recapitulate diabetic HER2+ human breast cancer. Additionally, our results defined the signaling pathways deregulated in HER2+ breast cancer under diabetic condition, which can be intervened by anti-insulin resistance therapy.

EGF Relays Signals to COP1 and Facilitates FOXO4 Degradation to Promote Tumorigenesis.

Forkhead-Box Class O 4 (FOXO4) is involved in critical biological functions, but its response to EGF-PKB/Akt signal regulation is not well characterized. Here, it is reported that FOXO4 levels are downregulated in response to EGF treatment, with concurrent elevation of COP9 Signalosome subunit 6 (CSN6) and E3 ubiquitin ligase constitutive photomorphogenic 1 (COP1) levels. Mechanistic studies show that CSN6 binds and regulates FOXO4 stability through enhancing the E3 ligase activity of COP1, and that COP1 directly interacts with FOXO4 through a VP motif on FOXO4 and accelerates the ubiquitin-mediated degradation of FOXO4. Metabolomic studies demonstrate that CSN6 expression leads to serine and glycine production. It is shown that FOXO4 directly binds and suppresses the promoters of serine-glycine-one-carbon (SGOC) pathway genes, thereby diminishing SGOC metabolism. Evidence shows that CSN6 can regulate FOXO4-mediated SGOC gene expression. Thus, these data suggest a link of CSN6-FOXO4 axis and ser/gly metabolism. Further, it is shown that CSN6-COP1-FOXO4 axis is deregulated in cancer and that the protein expression levels of CSN6 and FOXO4 can serve as prognostic markers for cancers. The results illustrate a pathway regulation of FOXO4-mediated serine/glycine metabolism through the function of CSN6-COP1 axis. Insights into this pathway may be strategically designed for therapeutic intervention in cancers.

Author Correction: A hypoxia-responsive TRAF6-ATM-H2AX signalling axis promotes HIF1α activation, tumorigenesis and metastasis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Analysis of Genomes and Transcriptomes of Hepatocellular Carcinomas Identifies Mutations and Gene Expression Changes in the Transforming Growth Factor-ß Pathway.

BACKGROUND & AIMS: Development of hepatocellular carcinoma (HCC) is associated with alterations in the transforming growth factor-beta (TGF-ß) signaling pathway, which regulates liver inflammation and can have tumor suppressor or promoter activities. Little is known about the roles of specific members of this pathway at specific of HCC development. We took an integrated approach to identify and validate the effects of changes in this pathway in HCC and identify therapeutic targets. METHODS: We performed transcriptome analyses for a total of 488 HCCs that include data from The Cancer Genome Atlas. We also screened 301 HCCs reported in the Catalogue of Somatic Mutations in Cancer and 202 from Cancer Genome Atlas for mutations in genome sequences. We expressed mutant forms of spectrin beta, non-erythrocytic 1 (SPTBN1) in HepG2, SNU398, and SNU475 cells and measured phosphorylation, nuclear translocation, and transcriptional activity of SMAD family member 3 (SMAD3). RESULTS: We found somatic mutations in at least 1 gene whose product is a member of TGF-ß signaling pathway in 38% of HCC samples. SPTBN1 was mutated in the largest proportion of samples (12 of 202, 6%). Unsupervised clustering of transcriptome data identified a group of HCCs with activation of the TGF-ß signaling pathway (increased transcription of genes in the pathway) and a group of HCCs with inactivation of TGF-ß signaling (reduced expression of genes in this pathway). Patients with tumors with inactivation of TGF-ß signaling had shorter survival times than patients with tumors with activation of TGF-ß signaling (P = .0129). Patterns of TGF-ß signaling correlated with activation of the DNA damage response and sirtuin signaling pathways. HepG2, SNU398, and SNU475 cells that expressed the D1089Y mutant or with knockdown of SPTBN1 had increased sensitivity to DNA crosslinking agents and reduced survival compared with cells that expressed normal SPTBN1 (controls). CONCLUSIONS: In genome and transcriptome analyses of HCC samples, we found mutations in genes in the TGF-ß signaling pathway in almost 40% of samples. These correlated with changes in expression of genes in the pathways; up-regulation of genes in this pathway would contribute to inflammation and fibrosis, whereas down-regulation would indicate loss of TGF-ß tumor suppressor activity. Our findings indicate that therapeutic agents for HCCs can be effective, based on genetic features of the TGF-ß pathway; agents that block TGF-ß should be used only in patients with specific types of HCCs.

A hypoxia-responsive TRAF6-ATM-H2AX signalling axis promotes HIF1α activation, tumorigenesis and metastasis.

The understanding of how hypoxia stabilizes and activates HIF1α in the nucleus with related oncogenic signals could revolutionize targeted therapy for cancers. Here, we find that histone H2AX displays oncogenic activity by serving as a crucial regulator of HIF1α signalling. H2AX interacts with HIF1α to prevent its degradation and nuclear export in order to allow successful VHL-independent HIF1α transcriptional activation. We show that mono-ubiquitylation and phosphorylation of H2AX, which are strictly mediated by hypoxia-induced E3 ligase activity of TRAF6 and ATM, critically regulate HIF1α-driven tumorigenesis. Importantly, TRAF6 and γH2AX are overexpressed in human breast cancer, correlate with activation of HIF1α signalling, and predict metastatic outcome. Thus, TRAF6 and H2AX overexpression and γH2AX-mediated HIF1α enrichment in the nucleus of cancer cells lead to overactivation of HIF1α-driven tumorigenesis, glycolysis and metastasis. Our findings suggest that TRAF6-mediated mono-ubiquitylation and subsequent phosphorylation of H2AX may serve as potential means for cancer diagnosis and therapy.

Obesity-associated NLRC4 inflammasome activation drives breast cancer progression.

Obesity is associated with an increased risk of developing breast cancer and is also associated with worse clinical prognosis. The mechanistic link between obesity and breast cancer progression remains unclear, and there has been no development of specific treatments to improve the outcome of obese cancer patients. Here we show that obesity-associated NLRC4 inflammasome activation/ interleukin (IL)-1 signalling promotes breast cancer progression. The tumour microenvironment in the context of obesity induces an increase in tumour-infiltrating myeloid cells with an activated NLRC4 inflammasome that in turn activates IL-1ß, which drives disease progression through adipocyte-mediated vascular endothelial growth factor A (VEGFA) expression and angiogenesis. Further studies show that treatment of mice with metformin inhibits obesity-associated tumour progression associated with a marked decrease in angiogenesis. This report provides a causal mechanism by which obesity promotes breast cancer progression and lays out a foundation to block NLRC4 inflammasome activation or IL-1ß signalling transduction that may be useful for the treatment of obese cancer patients.

Mutational Profiles Reveal an Aberrant TGF-ß-CEA Regulated Pathway in Colon Adenomas.

Mutational processes and signatures that drive early tumorigenesis are centrally important for early cancer prevention. Yet, to date, biomarkers and risk factors for polyps (adenomas) that inordinately and rapidly develop into colon cancer remain poorly defined. Here, we describe surprisingly high mutational profiles through whole-genome sequence (WGS) analysis in 2 of 4 pairs of benign colorectal adenoma tissue samples. Unsupervised hierarchical clustered transcriptomic analysis of a further 7 pairs of adenomas reveals distinct mutational signatures regardless of adenoma size. Transitional single nucleotide substitutions of C:G>T:A predominate in the adenoma mutational spectrum. Strikingly, we observe mutations in the TGF-ß pathway and CEA-associated genes in 4 out of 11 adenomas, overlapping with the Wnt pathway. Immunohistochemical labeling reveals a nearly 5-fold increase in CEA levels in 23% of adenoma samples with a concomitant loss of TGF-ß signaling. We also define a functional role by which the CEA B3 domain interacts with TGFBR1, potentially inactivating the tumor suppressor function of TGF-ß signaling. Our study uncovers diverse mutational processes underlying the transition from early adenoma to cancer. This has broad implications for biomarker-driven targeting of CEA/TGF-ß in high-risk adenomas and may lead to early detection of aggressive adenoma to CRC progression.

Kinetic Modeling and Constrained Reconstruction of Hyperpolarized [1-13C]-Pyruvate Offers Improved Metabolic Imaging of Tumors.

Hyperpolarized [1-(13)C]-pyruvate has shown tremendous promise as an agent for imaging tumor metabolism with unprecedented sensitivity and specificity. Imaging hyperpolarized substrates by magnetic resonance is unlike traditional MRI because signals are highly transient and their spatial distribution varies continuously over their observable lifetime. Therefore, new imaging approaches are needed to ensure optimal measurement under these circumstances. Constrained reconstruction algorithms can integrate prior information, including biophysical models of the substrate/target interaction, to reduce the amount of data that is required for image analysis and reconstruction. In this study, we show that metabolic MRI with hyperpolarized pyruvate is biased by tumor perfusion and present a new pharmacokinetic model for hyperpolarized substrates that accounts for these effects. The suitability of this model is confirmed by statistical comparison with alternates using data from 55 dynamic spectroscopic measurements in normal animals and murine models of anaplastic thyroid cancer, glioblastoma, and triple-negative breast cancer. The kinetic model was then integrated into a constrained reconstruction algorithm and feasibility was tested using significantly undersampled imaging data from tumor-bearing animals. Compared with naïve image reconstruction, this approach requires far fewer signal-depleting excitations and focuses analysis and reconstruction on new information that is uniquely available from hyperpolarized pyruvate and its metabolites, thus improving the reproducibility and accuracy of metabolic imaging measurements.

COP9 signalosome subunit 6 (CSN6) regulates E6AP/UBE3A in cervical cancer.

Cervical cancer is one of the leading causes of cancer death in women. Human papillomaviruses (HPVs) are the major cause in almost 99.7% of cervical cancer. E6 oncoprotein of HPV and E6-associated protein (E6AP) are critical in causing p53 degradation and malignancy. Understanding the E6AP regulation is critical to develop treating strategy for cervical cancer patients. The COP9 signalosome subunit 6 (CSN6) is involved in ubiquitin-mediated protein degradation. We found that both CSN6 and E6AP are overexpressed in cervical cancer. We characterized that CSN6 associated with E6AP and stabilized E6AP expression by reducing E6AP poly-ubiquitination, thereby regulating p53 activity in cell proliferation and apoptosis. Mechanistic studies revealed that CSN6-E6AP axis can be regulated by EGF/Akt signaling. Furthermore, inhibition of CSN6-E6AP axis hinders cervical cancer growth in mice. Taken together, our results indicate that CSN6 is a positive regulator of E6AP and is important for cervical cancer development.

CSN6 positively regulates c-Jun in a MEKK1-dependent manner.

c-Jun is a proto-oncoprotein that is commonly overexpressed in many types of cancer and is believed to regulate cell proliferation, the cell cycle, and apoptosis by controlling AP-1 activity. Understanding the c-Jun regulation is important to develop treatment strategy for cancer. The COP9 signalosome subunit 6 (CSN6) plays a critical role in ubiquitin-mediated protein degradation. MEKK1 is a serine/threonine kinase and E3 ligase containing PHD/RING domain involved in c-Jun ubiquitination. Here, we show that CSN6 associates with MEKK1 and reduces MEKK1 expression level by facilitating the ubiquitin-mediated degradation of MEKK1. Also we show that CSN6 overexpression diminishes MEKK1-mediated c-Jun ubiquitination, which is manifested in mitigating osmotic stress-mediated c-Jun downregulation. Thus, CSN6 is involved in positively regulating the stability of c-Jun. Overexpression of CSN6 correlates with the upregulation of c-Jun target gene expression in cancer. These findings provide new insight into CSN6-MEKK1-c-Jun axis in tumorigenesis.

Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma.

Adrenocortical carcinoma is a rare malignancy with poor prognosis and limited response to chemotherapy. Hepatocyte growth factor (HGF) and its receptor cMET augment cancer growth and resistance to chemotherapy, but their role in adrenocortical carcinoma has not been examined. In this study, we investigated the association between HGF/cMET expression and cancer hallmarks of adrenocortical carcinoma. Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in human adrenocortical carcinoma samples was positively associated with cancer-related biologic processes, including proliferation and angiogenesis, and negatively correlated with apoptosis. Accordingly, treatment of adrenocortical carcinoma cells with exogenous HGF resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA-mediated knockdown or pharmacologic inhibition of cMET suppressed cell proliferation and tumor growth. Moreover, exposure of cells to mitotane, cisplatin, or radiation rapidly induced pro-cMET expression and was associated with an enrichment of genes (e.g., CYP450 family) related to therapy resistance, further implicating cMET in the anticancer drug response. Together, these data suggest an important role for HGF/cMET signaling in adrenocortical carcinoma growth and resistance to commonly used treatments. Targeting cMET, alone or in combination with other drugs, could provide a breakthrough in the management of this aggressive cancer.

COP1 enhances ubiquitin-mediated degradation of p27Kip1 to promote cancer cell growth.

p27 is a critical CDK inhibitor involved in cell cycle regulation, and its stability is critical for cell proliferation. Constitutive photomorphogenic 1 (COP1) is a RING-containing E3 ubiquitin ligase involved in regulating important target proteins for cell growth, but its biological activity in cell cycle progression is not well characterized. Here, we report that p27Kip1 levels are accumulated in G1 phase, with concurrent reduction of COP1 levels. Mechanistic studies show that COP1 directly interacts with p27 through a VP motif on p27 and functions as an E3 ligase of p27 to accelerate the ubiquitin-mediated degradation of p27. Also, COP1-p27 axis deregulation is involved in tumorigenesis. These findings define a new mechanism for posttranslational regulation of p27 and provide insight into the characteristics of COP1-overexpressing cancers.

The cell cycle regulator 14-3-3σ opposes and reverses cancer metabolic reprogramming.

Extensive reprogramming of cellular energy metabolism is a hallmark of cancer. Despite its importance, the molecular mechanism controlling this tumour metabolic shift remains not fully understood. Here we show that 14-3-3σ regulates cancer metabolic reprogramming and protects cells from tumorigenic transformation. 14-3-3σ opposes tumour-promoting metabolic programmes by enhancing c-Myc poly-ubiquitination and subsequent degradation. 14-3-3σ demonstrates the suppressive impact on cancer glycolysis, glutaminolysis, mitochondrial biogenesis and other major metabolic processes of tumours. Importantly, 14-3-3σ expression levels predict overall and recurrence-free survival rates, tumour glucose uptake and metabolic gene expression in breast cancer patients. Thus, these results highlight that 14-3-3σ is an important regulator of tumour metabolism, and loss of 14-3-3σ expression is critical for cancer metabolic reprogramming. We anticipate that pharmacologically elevating the function of 14-3-3σ in tumours could be a promising direction for targeted anticancer metabolism therapy development in future.

Regulating the stability and localization of CDK inhibitor p27(Kip1) via CSN6-COP1 axis.

The COP9 signalosome subunit 6 (CSN6), which is involved in ubiquitin-mediated protein degradation, is overexpressed in many types of cancer. CSN6 is critical in causing p53 degradation and malignancy, but its target in cell cycle progression is not fully characterized. Constitutive photomorphogenic 1 (COP1) is an E3 ubiquitin ligase associating with COP9 signalosome to regulate important target proteins for cell growth. p27 is a critical G1 CDK inhibitor involved in cell cycle regulation, but its upstream regulators are not fully characterized. Here, we show that the CSN6-COP1 link is regulating p27(Kip1) stability, and that COP1 is a negative regulator of p27(Kip1). Ectopic expression of CSN6 can decrease the expression of p27(Kip1), while CSN6 knockdown leads to p27(Kip1) stabilization. Mechanistic studies show that CSN6 interacts with p27(Kip1) and facilitates ubiquitin-mediated degradation of p27(Kip1). CSN6-mediated p27 degradation depends on the nuclear export of p27(Kip1), which is regulated through COP1 nuclear exporting signal. COP1 overexpression leads to the cytoplasmic distribution of p27, thereby accelerating p27 degradation. Importantly, the negative impact of COP1 on p27 stability contributes to elevating expression of genes that are suppressed through p27 mediation. Kaplan-Meier analysis of tumor samples demonstrates that high COP1 expression was associated with poor overall survival. These data suggest that tumors with CSN6/COP1 deregulation may have growth advantage by regulating p27 degradation and subsequent impact on p27 targeted genes.

CSN6 drives carcinogenesis by positively regulating Myc stability.

Cullin-RING ubiquitin ligases (CRLs) are critical in ubiquitinating Myc, while COP9 signalosome (CSN) controls neddylation of Cullin in CRL. The mechanistic link between Cullin neddylation and Myc ubiquitination/degradation is unclear. Here we show that Myc is a target of the CSN subunit 6 (CSN6)-Cullin signalling axis and that CSN6 is a positive regulator of Myc. CSN6 enhanced neddylation of Cullin-1 and facilitated autoubiquitination/degradation of Fbxw7, a component of CRL involved in Myc ubiquitination, thereby stabilizing Myc. Csn6 haplo-insufficiency decreased Cullin-1 neddylation but increased Fbxw7 stability to compromise Myc stability and activity in an Eµ-Myc mouse model, resulting in decelerated lymphomagenesis. We found that CSN6 overexpression, which leads to aberrant expression of Myc target genes, is frequent in human cancers. Together, these results define a mechanism for the regulation of Myc stability through the CSN-Cullin-Fbxw7 axis and provide insights into the correlation of CSN6 overexpression with Myc stabilization/activation during tumorigenesis.