Specificity protein 1 induces the expression of angiomotin in response to IL-6/STAT3 activation to mediate YAP-dependent growth of breast cancer cells

Indiana University-Purdue University Indianapolis (IUPUI)Chronic inflammation is a major driver of tumor progression in over fifty percent of breast cancers. Tumors activate inflammatory processes by secreting factors that recruit and trigger inflammatory cells to release cytokines such as Interleukin 6 (IL-6). IL-6 stimulates the activity of signal transducers and activators of transcription 3 (STAT3), a transcription factor that has been extensively studied for its role in promoting breast cancer. Recently, downregulated HIPPO signaling was shown to drive the pro-growth effects of IL 6. Reduced HIPPO signaling allows for the nuclear translocation of transcriptional co-activator yes associated protein (YAP), implicating IL-6 in the co-activation of several transcription factors such as the TEADs that trigger pro growth programs. While IL-6/STAT3 stimulation has been shown to increase YAP activity, the mechanism driving this remains undocumented. The Angiomotins (Amots) are adapters of the HIPPO pathway that directly bind and regulate YAP activity. Molecular characterization of Amot transcriptional regulation unexpectedly revealed a single promoter controlling the expression of its two major isoforms: Amot 130 and Amot 80. Through immunofluorescent analysis, this study found that total Amot levels were elevated across multiple breast tumor subtypes and highest in samples with increased presence of stromal inflammatory cells. Further, the induction of total Amot expression by IL 6 was found to be essential for YAP dependent growth of breast cancer cells. The activation of Amot transcription by IL-6 was found to be through Specificity Protein 1 (Sp1), a transcription factor that is activated by STAT3. This work connects the activation of YAP1 by IL-6/STAT3 through the elevation of Amot expression by Sp1. Taken together, this explains a new avenue whereby breast cancer cells acquire enhanced oncogenic properties in response to inflammatory signaling

Combination therapy in a xenograft model of glioblastoma: enhancement of the antitumor activity of temozolomide by an MDM2 antagonist

OBJECTIVE Improvement in treatment outcome for patients with glioblastoma multiforme (GBM) requires a multifaceted approach due to dysregulation of numerous signaling pathways. The murine double minute 2 (MDM2) protein may fulfill this requirement because it is involved in the regulation of growth, survival, and invasion. The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM. METHODS The combination of TMZ with the MDM2 protein-protein interaction inhibitor nutlin3a was evaluated for effects on cell growth, p53 pathway activation, expression of DNA repair proteins, and invasive properties. In vivo efficacy was assessed in xenograft models of human GBM. RESULTS In combination, TMZ/nutlin3a was additive to synergistic in decreasing growth of wild-type p53 GBM cells. Pharmacodynamic studies demonstrated that inhibition of cell growth following exposure to TMZ/nutlin3a correlated with: 1) activation of the p53 pathway, 2) downregulation of DNA repair proteins, 3) persistence of DNA damage, and 4) decreased invasion. Pharmacokinetic studies indicated that nutlin3a was detected in human intracranial tumor xenografts. To assess therapeutic potential, efficacy studies were conducted in a xenograft model of intracranial GBM by using GBM cells derived from a recurrent wild-type p53 GBM that is highly TMZ resistant (GBM10). Three 5-day cycles of TMZ/nutlin3a resulted in a significant increase in the survival of mice with GBM10 intracranial tumors compared with single-agent therapy. CONCLUSIONS Modulation of MDM2/p53-associated signaling pathways is a novel approach for decreasing TMZ resistance in GBM. To the authors' knowledge, this is the first study in a humanized intracranial patient-derived xenograft model to demonstrate the efficacy of combining front-line TMZ therapy and an inhibitor of MDM2 protein-protein interactions

Emerging Roles for SIRT5 in Metabolism and Cancer

Significance: Developing evidence in the literature suggests that sirtuin 5 (SIRT5) may be involved in metabolic reprogramming, an emerging hallmark of cancer by which neoplastic cells reconfigure their metabolism to support the anabolic demands of rapid cell division. SIRT5 is one of the seven members of the nicotinamide adenine dinucleotide-dependent sirtuin family of lysine deacetylases. It removes succinyl, malonyl, and glutaryl groups from protein targets within the mitochondrial matrix and other subcellular compartments. SIRT5 substrates include a number of proteins integral to metabolism. Recent Advances: New work has begun to elucidate the roles of SIRT5 in glycolysis, tricarboxylic acid cycle, fatty acid oxidation, nitrogen metabolism, pentose phosphate pathway, antioxidant defense, and apoptosis. Critical Issues: In this study, we summarize biological functions of SIRT5 reported in normal tissues and in cancer and discuss potential mechanisms whereby SIRT5 may impact tumorigenesis, particularly focusing on its reported roles in metabolic reprogramming. Finally, we review current efforts to target SIRT5 pharmacologically. Future Directions: The biological significance of SIRT5 has been elucidated in the context of only an extremely small fraction of its targets and interactors. There is no doubt that further studies in this area will provide a wealth of insights into functions of SIRT5 and its targets in normal and neoplastic cells. Antioxid. Redox Signal. 28, 677–690

The deacylase SIRT5 supports melanoma viability by influencing chromatin dynamics

Cutaneous melanoma remains the most lethal skin cancer, and ranks third among all malignancies in terms of years of life lost. Despite the advent of immune checkpoint and targeted therapies, only roughly half of patients with advanced melanoma achieve a durable remission. Sirtuin 5 (SIRT5) is a member of the sirtuin family of protein deacylases that regulates metabolism and other biological processes. Germline Sirt5 deficiency is associated with mild phenotypes in mice. Here we showed that SIRT5 was required for proliferation and survival across all cutaneous melanoma genotypes tested, as well as uveal melanoma, a genetically distinct melanoma subtype that arises in the eye and is incurable once metastatic. Likewise, SIRT5 was required for efficient tumor formation by melanoma xenografts and in an autochthonous mouse Braf Pten-driven melanoma model. Via metabolite and transcriptomic analyses, we found that SIRT5 was required to maintain histone acetylation and methylation levels in melanoma cells, thereby promoting proper gene expression. SIRT5-dependent genes notably included MITF, a key lineage-specific survival oncogene in melanoma, and the c-MYC proto-oncogene. SIRT5 may represent a druggable genotype-independent addiction in melanoma