Mitchell Fane

Pin1 promotes neuronal death in stroke by stabilizing Notch intracellular domain

Stroke is a leading cause of mortality and disability. The peptidyl‐prolyl cis/trans isomerase Pin1 regulates factors involved in cell growth. Recent evidence has shown that Pin1 plays a major role in apoptosis. However, the role of Pin1 in ischemic stroke remains to be investigated.

NFIB Mediates BRN2 Driven Melanoma Cell Migration and Invasion Through Regulation of EZH2 and MITF

While invasion and metastasis of tumour cells are the principle factor responsible for cancer related deaths, the mechanisms governing the process remain poorly defined. Moreover, phenotypic divergence of sub-populations of tumour cells is known to underpin alternative behaviors linked to tumour progression such as proliferation, survival and invasion. In the context of melanoma, heterogeneity between two transcription factors, BRN2 and MITF, has been associated with phenotypic switching between predominantly invasive and proliferative behaviors respectively. Epigenetic changes, in response to external cues, have been proposed to underpin this process, however the mechanism by which the phenotypic switch occurs is unclear. Here we report the identification of the NFIB transcription factor as a novel downstream effector of BRN2 function in melanoma cells linked to the migratory and invasive characteristics of these cells. Furthermore, the function of NFIB appears to drive an invasive phenotype through an epigenetic mechanism achieved via the upregulation of the polycomb group protein EZH2. A notable target of NFIB mediated up-regulation of EZH2 is decreased MITF expression, which further promotes a less proliferative, more invasive phenotype. Together our data reveal that NFIB has the ability to promote dynamic changes in the chromatin state of melanoma cells to facilitate migration, invasion and metastasis.

Nuclear factor one transcription factors as epigenetic regulators in cancer

Tumour heterogeneity poses a distinct obstacle to therapeutic intervention. While the initiation of tumours across various physiological systems is frequently associated with signature mutations in genes that drive proliferation and bypass senescence, increasing evidence suggests that tumour progression and clonal diversity is driven at an epigenetic level. The tumour microenvironment plays a key role in driving diversity as cells adapt to demands imposed during tumour growth, and is thought to drive certain subpopulations back to a stem cell‐like state. This stem cell‐like phenotype primes tumour cells to react to external cues via the use of developmental pathways that facilitate changes in proliferation, migration and invasion. Because the dynamism of this stem cell‐like state requires constant chromatin remodelling and rapid alterations at regulatory elements, it is of great therapeutic interest to identify the cell‐intrinsic factors that confer these epigenetic changes that drive tumour progression. The nuclear factor one (NFI) family are transcription factors that play an important role in the development of many mammalian organ systems. While all four family members have been shown to act as either oncogenes or tumour suppressors across various cancer models, evidence has emerged implicating them as key epigenetic regulators during development and within tumours. Notably, NFIs have also been shown to regulate chromatin accessibility at distal regulatory elements that drive tumour cell dissemination and metastasis. Here we summarize the role of the NFIs in cancer, focusing largely on the potential mechanisms associated with chromatin remodelling and epigenetic modulation of gene expression.

BRN2, a POUerful driver of melanoma phenotype switching and metastasis

The POU domain family of transcription factors play a central role in embryogenesis and are highly expressed in neural crest cells and the developing brain. BRN2 is a class III POU domain protein that is a key mediator of neuroendocrine and melanocytic development and differentiation. While BRN2 is a central regulator in numerous developmental programs, it has also emerged as a major player in the biology of tumourigenesis. In melanoma, BRN2 has been implicated as one of the master regulators of the acquisition of invasive behaviour within the phenotype switching model of progression. As a mediator of melanoma cell phenotype switching, it coordinates the transition to a dedifferentiated, slow cycling and highly motile cell type. Its inverse expression relationship with MITF is believed to mediate tumour progression and metastasis within this model. Recent evidence has now outlined a potential epigenetic switching mechanism in melanoma cells driven by BRN2 expression that induces melanoma cell invasion. We summarize the role of BRN2 in tumour cell dissemination and metastasis in melanoma, while also examining it as a potential metastatic regulator in other tumour models.

Four! Drivers of melanoma differentiation-When to use iron

Tumour heterogeneity is one of the fundamental challenges underlying progression and treatment of all cancers. Heterogenous subpopulations are a consequence of tumour cells adapting to intrinsic oncogene and extrinsic microenvironmental-induced stressors that drive differences in the proliferative, invasive, and metabolic characteristics of cells. While there are clear genetic factors such as somatic mutation that underlie the appearance of heterogenous subpopulations, growing evidence suggests that much of the heterogeneity seen at the phenotypic level exists due to changes at the gene expression and epigenetic level. This article is protected by copyright. All rights reserved.

Bad company: Microenvironmentally mediated resistance to targeted therapy in melanoma

This review will focus on the role of the tumor microenvironment (TME) in the development of drug resistance in melanoma. Resistance to mitogen‐activated protein kinase inhibitors (MAPKi) in melanoma is observed months after treatment, a phenomenon that is often attributed to the incredible plasticity of melanoma cells but may also depend on the TME. The TME is unique in its cellular composition—it contains fibroblasts, immune cells, endothelial cells, adipocytes, and among others. In addition, the TME provides “non‐homeostatic” levels of oxygen, nutrients (hypoxia and metabolic stress), and extracellular matrix proteins, creating a pro‐tumorigenic niche that drives resistance to MAPKi treatment. In this review, we will focus on how changes in the tumor microenvironment regulate MAPKi resistance.

NR4A2 Promotes DNA Double-strand Break Repair Upon Exposure to UVR

Exposure of melanocytes to ultraviolet radiation (UVR) induces the formation of UV lesions that can produce deleterious effects in genomic DNA. Encounters of replication forks with unrepaired UV lesions can lead to several complex phenomena, such as the formation of DNA double-strand breaks (DSBs). The NR4A family of nuclear receptors are transcription factors that have been associated with mediating DNA repair functions downstream of the MC1R signaling pathway in melanocytes. In particular, emerging evidence shows that upon DNA damage, the NR4A2 receptor can translocate to sites of UV lesion by mechanisms requiring post-translational modifications within the N-terminal domain and at a serine residue in the DNA-binding domain at position 337. Following this, NR4A2 aids in DNA repair by facilitating chromatin relaxation, allowing accessibility for DNA repair machinery. Using A2058 and HT144 melanoma cells engineered to stably express wild-type or mutant forms of the NR4A2 proteins, we reveal that the expression of functional NR4A2 is associated with elevated cytoprotection against UVR. Conversely, knockdown of NR4A2 expression by siRNA results in a significant loss of cell viability after UV insult. By analyzing the kinetics of the ensuing 53BP1 and RAD51 foci following UV irradiation, we also reveal that the expression of mutant NR4A2 isoforms, lacking the ability to translocate, transactivate, or undergo phosphorylation, display compromised repair capacity. Implications: These data expand the understanding of the mechanism by which the NR4A2 nuclear receptor can facilitate DNA DSB repair. Mol Cancer Res; 15(9); 1184–96. ©2017 AACR.

Melanoma tumor sub-populations are defined by MITF expression, and exhibit enhanced proliferation and characteristics of an EMT

HUMMER, DOUGLAS ANDREW. Community College Presidential Change from the Department Leader’s Perspective: A Case Study. (Under the direction of Dr. Diane Chapman). Academic department leaders are the least studied level of management in higher education, yet they play a fundamental role in transforming the vision and goals of executive leadership into reality (Gonaim, 2016). Academic department leaders play such a role because as a group, they influence the largest part of the employee population at a college; the faculty (Stringer, 2002; Tierney, 1999). Since the ability to create lasting change is one of the core qualities of a highly effective community college president (The Aspen Institute & Achieving the Dream, 2013), it is important to understand how the strategies, tactics, and actions employed by the executive leadership of an institution of higher learning shape the perceptions academic department leaders have of their workplace. This study took a qualitative approach to understanding these perceptions during the first few months of new president’s administration at a large community college in the southeast US. A transcendental phenomenological (Husserl, 2004) lens and case study methodologies were used to collect and analyze structural and textural data to describe the perceptions and interpretations academic department leaders had of this presidential change phenomenon. The case study itself provided the structural description, or context of the phenomenon, and semi-structured interviews were used to give voice to the academic department leaders that participated in the study. An analysis of the data revealed a number of themes that addressed the research questions asked in this study. These themes led to the following findings in this study. Listening sessions initiated by the new president and the hiring process that brought him to the college were identified as major influencing events in creating a positive impression of this new executive and his vision for the future of the institution. This positive impression is a contributor to creating an organizational climate ready to accept change. Other themes that emerged revolved around executive leadership’s support, communication issues, the hierarchical levels of management, changes that were initiated, and the fear to speak up. The findings from this study can be used by many community colleges as they hire new presidents and prepare for the changes new executives bring. The findings can also be used by any college approaching a major change initiative. The presidential change phenomenon will affect as many as four out of every five community colleges over the next 10 years (Phillippe, 2016). Presidential changes and other major change initiatives that community colleges experience will provide many opportunities to repeat this study and share the findings with others experiencing the same phenomenon.