MYC-driven epigenetic reprogramming favors the onset of tumorigenesis by inducing a stem cell-like state

Breast cancer consists of highly heterogeneous tumors, whose cell of origin and driver oncogenes are difficult to be uniquely defined. Here we report that MYC acts as tumor reprogramming factor in mammary epithelial cells by inducing an alternative epigenetic program, which triggers loss of cell identity and activation of oncogenic pathways. Overexpression of MYC induces transcriptional repression of lineage-specifying transcription factors, causing decommissioning of luminal-specific enhancers. MYC-driven dedifferentiation supports the onset of a stem cell-like state by inducing the activation of de novo enhancers, which drive the transcriptional activation of oncogenic pathways. Furthermore, we demonstrate that the MYC-driven epigenetic reprogramming favors the formation and maintenance of tumor-initiating cells endowed with metastatic capacity. This study supports the notion that MYC-driven tumor initiation relies on cell reprogramming, which is mediated by the activation of MYC-dependent oncogenic enhancers, thus establishing a therapeutic rational for treating basal-like breast cancers

Eyes as Gateways for Environmental Light to the Substantia Nigra: Relevance in Parkinson’s Disease

Recent data indicates that prolonged bright light exposure of rats induces production of neuromelanin and reduction of tyrosine hydroxylase positive neurons in the substantia nigra. This effect was the result of direct light reaching the substantia nigra and not due to alteration of circadian rhythms. Here, we measured the spectrum of light reaching the substantia nigra in rats and analysed the pathway that light may take to reach this deep brain structure in humans. Wavelength range and light intensity, emitted from a fluorescent tube, were measured, using a stereotaxically implanted optical fibre in the rat mesencephalon. The hypothetical path of environmental light from the eye to the substantia nigra in humans was investigated by computed tomography and magnetic resonance imaging. Light with wavelengths greater than 600 nm reached the rat substantia nigra, with a peak at 709 nm. Eyes appear to be the gateway for light to the mesencephalon since covering the eyes with aluminum foil reduced light intensity by half. Using computed tomography and magnetic resonance imaging of a human head, we identified the eye and the superior orbital fissure as possible gateways for environmental light to reach the mesencephalon

Trastuzumab-induced corneal ulceration: successful no-drug treatment of a "blind" side effect in a case report

BACKGROUND: We report the first successful treatment of limbal lesions and corneal erosion experienced by a breast cancer patient undergoing trastuzumab treatment. CASE PRESENTATION: A 49-year-old Caucasian woman with early stage breast cancer was treated with adjuvant trastuzumab and subsequently showed persistent bilateral corneal marginal infiltrates resistant to topical steroid and antibiotic treatment. Autologous serum was applied in the conjunctival sac as an experimental treatment to antagonize the inhibitory effect of the HER2 receptor antibody on the corneal epithelial cells. Topical application of autologous serum led to rapid improvement of the ulcerative keratitis, with complete healing of the corneal defect after 7 days. Continued administration of the serum allowed the resumption of trastuzumab therapy without any further side effects. CONCLUSIONS: Persistent bilateral corneal marginal infiltrates may occasionally arise as a side effect of trastuzumab treatment. Topical medication with autologous serum may be an effective therapeutic option for the ocular side effects of trastuzumab therapy

SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring

Mutations in one SETD5 allele are genetic causes of intellectual disability and autistic spectrum disorders. However, the mechanisms by which SETD5 regulates brain development and function remain largely elusive. Herein, we found that Setd5 haploinsufficiency impairs the proliferative dynamics of neural progenitors and synaptic wiring of neurons, ultimately resulting in behavioral deficits in mice. Mechanistically, Setd5 inactivation in neural stem cells, zebrafish, and mice equally affects genome-wide levels of H3K36me3 on active gene bodies. Notably, we demonstrated that SETD5 directly deposits H3K36me3, which is essential to allow on-time RNA elongation dynamics. Hence, Setd5 gene loss leads to abnormal transcription, with impaired RNA maturation causing detrimental effects on gene integrity and splicing. These findings identify SETD5 as a fundamental epigenetic enzyme controlling the transcriptional landscape in neural progenitors and their derivatives and illuminate the molecular events that connect epigenetic defects with neuronal dysfunctions at the basis of related human diseases

A Myc-driven self-reinforcing regulatory network maintains mouse embryonic stem cell identity

Stem cell identity depends on the integration of extrinsic and intrinsic signals, which directly influence the maintenance of their epigenetic state. Although Myc transcription factors play a major role in stem cell self-renewal and pluripotency, their integration with signalling pathways and epigenetic regulators remains poorly defined. We addressed this point by profiling the gene expression and epigenetic pattern in ESCs whose growth depends on conditional Myc activity. Here we show that Myc potentiates the Wnt/β-catenin signalling pathway, which cooperates with the transcriptional regulatory network in sustaining ESC self-renewal. Myc activation results in the transcriptional repression of Wnt antagonists through the direct recruitment of PRC2 on these targets. The consequent potentiation of the autocrine Wnt/β-catenin signalling induces the transcriptional activation of the endogenous Myc family members, which in turn activates a Myc-driven self-reinforcing circuit. Thus, our data unravel a Myc-dependent self-propagating epigenetic memory in the maintenance of ESC self-renewal capacity.ISSN:2041-172

Romidepsin (FK228) fails in counteracting the transformed phenotype of rhabdomyosarcoma cells but efficiently radiosensitizes, in vitro and in vivo, the alveolar phenotype subtype

PURPOSE Herein we describe the in vitro and in vivo activity of FK228 (Romidepsin), an inhibitor of class I HDACs, in counteracting and radiosensitizing embryonal (ERMS, fusion-negative) and alveolar (ARMS, fusion-positive) rhabdomyosarcoma (RMS).METHODS RH30 (ARMS, fusion-positive) and RD (ERMS, fusion-negative) cell lines and human multipotent mesenchymal stromal cells (HMSC) were used. Flow cytometry analysis, RT-qPCR, western blotting and enzymatic assays were performed. Irradiation was delivered by using an x-6 MV photon linear accelerator. FK228 (1.2 mg/kg) in vivo activity, combined or not with radiation therapy (2 Gy), was assessed in murine xenografts.RESULTS Compared to HMSC, RMS expressed low levels of class I HDACs. In vitro, FK228, as single agents, reversibly downregulated class I HDACs expression and activity, and induced oxidative stress, DNA damage and a concomitant growth arrest associated to PARP-1-mediated transient non-apoptotic cell death. Surviving cells upregulated the expression of cyclin A, B, D1, p27, Myc and activated PI3K/Akt/mTOR and MAPK signaling, known to be differently involved in cancer chemoresistance. Interestingly, while no radiosensitizing effects were detected, in vitro or in vivo, on RD cells, FK228 markedly radiosensitized RH30 cells by impairing antioxidant and DSBs repair pathways in vitro. Further, FK228 when combined with RT in vivo significantly reduced tumor mass in mouse RH30 xenografts.CONCLUSION FK228 did not show antitumor activity as single agent whilst its combination with RT resulted in radiosensitization of fusion-positive RMS cells, thus representing a possible strategy for the treatment of the most aggressive RMS subtype