Cancer-associated fibroblasts promote cancer stemness by inducing expression of the chromatin-modifying protein CBX4 in squamous cell carcinoma.

The chromobox-containing protein CBX4 is an important regulator of epithelial cell proliferation and differentiation, and has been implicated in several cancer types. The cancer stem cell (CSC) population is a key driver of metastasis and recurrence. The undifferentiated, plastic state characteristic of CSCs relies on cues from the microenvironment. Cancer-associated fibroblasts (CAFs) are a major component of the microenvironment that can influence the CSC population through the secretion of extracellular matrix and a variety of growth factors. Here we show CBX4 is a critical regulator of the CSC phenotype in squamous cell carcinomas of the skin and hypopharynx. Moreover, CAFs can promote the expression of CBX4 in the CSC population through the secretion of interleukin-6 (IL-6). IL-6 activates JAK/STAT3 signaling to increase ∆Np63α-a key transcription factor that is essential for epithelial stem cell function and the maintenance of proliferative potential that is capable of regulating CBX4. Targeting the JAK/STAT3 axis or CBX4 directly suppresses the aggressive phenotype of CSCs and represents a novel opportunity for therapeutic intervention.

Chd5 Regulates the Transcription Factor Six3 to Promote Neuronal Differentiation.

Chromodomain helicase DNA-binding protein 5 (Chd5) is an ATP-dependent chromatin remodeler that promotes neuronal differentiation. However, the mechanism behind the action of Chd5 during neurogenesis is not clearly understood. Here we use transcriptional profiling of cells obtained from Chd5 deficient mice at early and late stages of neuronal differentiation to show that Chd5 regulates neurogenesis by directing stepwise transcriptional changes. During early stages of neurogenesis, Chd5 promotes expression of the proneural transcription factor Six3 to repress Wnt5a, a non-canonical Wnt ligand essential for the maturation of neurons. This previously unappreciated ability of Chd5 to transcriptionally repress neuronal maturation factors is critical for both lineage specification and maturation. Thus, Chd5 facilitates early transcriptional changes in neural stem cells, thereby initiating transcriptional programs essential for neuronal fate specification.

BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network.

Inhibition of the tumour suppressive function of p53 (encoded by TP53) is paramount for cancer development in humans. However, p53 remains unmutated in the majority of cases of glioblastoma (GBM)-the most common and deadly adult brain malignancy1,2. Thus, how p53-mediated tumour suppression is countered in TP53 wild-type (TP53WT) GBM is unknown. Here we describe a GBM-specific epigenetic mechanism in which the chromatin regulator bromodomain-containing protein 8 (BRD8) maintains H2AZ occupancy at p53 target loci through the EP400 histone acetyltransferase complex. This mechanism causes a repressive chromatin state that prevents transactivation by p53 and sustains proliferation. Notably, targeting the bromodomain of BRD8 displaces H2AZ, enhances chromatin accessibility and engages p53 transactivation. This in turn enforces cell cycle arrest and tumour suppression in TP53WT GBM. In line with these findings, BRD8 is highly expressed with H2AZ in proliferating single cells of patient-derived GBM, and is inversely correlated with CDKN1A, a canonical p53 target that encodes p21 (refs. 3,4). This work identifies BRD8 as a selective epigenetic vulnerability for a malignancy for which treatment has not improved for decades. Moreover, targeting the bromodomain of BRD8 may be a promising therapeutic strategy for patients with TP53WT GBM.

EZH2 regulates a SETDB1/ΔNp63α axis via RUNX3 to drive a cancer stem cell phenotype in squamous cell carcinoma.

Enhancer of zeste homolog 2 (EZH2) and SET domain bifurcated 1 (SETDB1, also known as ESET) are oncogenic methyltransferases implicated in a number of human cancers. These enzymes typically function as epigenetic repressors of target genes by methylating histone H3 K27 and H3-K9 residues, respectively. Here, we show that EZH2 and SETDB1 are essential to proliferation in 3 SCC cell lines, HSC-5, FaDu, and Cal33. Additionally, we find both of these proteins highly expressed in an aggressive stem-like SCC sub-population. Depletion of either EZH2 or SETDB1 disrupts these stem-like cells and their associated phenotypes of spheroid formation, invasion, and tumor growth. We show that SETDB1 regulates this SCC stem cell phenotype through cooperation with ΔNp63α, an oncogenic isoform of the p53-related transcription factor p63. Furthermore, EZH2 is upstream of both SETDB1 and ΔNp63α, activating these targets via repression of the tumor suppressor RUNX3. We show that targeting this pathway with inhibitors of EZH2 results in activation of RUNX3 and repression of both SETDB1 and ΔNp63α, antagonizing the SCC cancer stem cell phenotype. This work highlights a novel pathway that drives an aggressive cancer stem cell phenotype and demonstrates a means of pharmacological intervention.

BRD4 Regulates Transcription Factor ΔNp63α to Drive a Cancer Stem Cell Phenotype in Squamous Cell Carcinomas.

Bromodomain containing protein 4 (BRD4) plays a critical role in controlling the expression of genes involved in development and cancer. Inactivation of BRD4 inhibits cancer growth, making it a promising anticancer drug target. The cancer stem cell (CSC) population is a key driver of recurrence and metastasis in patients with cancer. Here we show that cancer stem-like cells can be enriched from squamous cell carcinomas (SCC), and that these cells display an aggressive phenotype with enhanced stem cell marker expression, migration, invasion, and tumor growth. BRD4 is highly elevated in this aggressive subpopulation of cells, and its function is critical for these CSC-like properties. Moreover, BRD4 regulates ΔNp63α, a key transcription factor that is essential for epithelial stem cell function that is often overexpressed in cancers. BRD4 regulates an EZH2/STAT3 complex that leads to increased ΔNp63α-mediated transcription. Targeting BRD4 in human SCC reduces ΔNp63α, leading to inhibition of spheroid formation, migration, invasion, and tumor growth. These studies identify a novel BRD4-regulated signaling network in a subpopulation of cancer stem-like cells, elucidating a possible avenue for effective therapeutic intervention. SIGNIFICANCE: This study identifies a signaling cascade driven by BRD4 that upregulates ΔNp63α to promote cancer stem-like properties, which has potential therapeutic implications for the treatment of squamous cell carcinomas.

Evaluación de la capacidad antioxidante y compuestos bioactivos de tumbo (Passiflora mollissima) y cerezo (Prunus serotina)

Objetivo: Determinar el contenido de compuestos bioactivos y la capacidad antioxidante de los frutos tumbo (Passiflora mollissima) y cerezo (Prunus serotina). Materiales y métodos: Estudio analítico, experimental, longitudinal y prospectivo. Los frutos cerezo y tumbo se recolectaron en las regiones de Cusco, Moquegua y Arequipa. La técnica de Folin-Ciocalteu fue empleada para determinar el contenido de fenoles, y el cloruro de aluminio se utilizó para calcular los flavonoides. La actividad antioxidante se evaluó mediante las técnicas Ferric Reducing Ability of Plasma (FRAP), 2,2-difenil-picril-hidrazil (DPPH) y sustancias reactivas al ácido tiobarbitúrico (TBARS). Para estudiar el efecto hepatoprotector de las frutas, utilizamos ratas albinas que se clasificaron en un grupo control negativo, un grupo control positivo y cuatro grupos experimentales. Resultados: La mayor concentración de fenoles totales y flavonoides se encontró en el tumbo de la región Cusco (Quechua) (fenoles totales: 584,94 ± 134,62 mg EAG / 100 g y flavonoides :445,62 ± 7,94 mg EQ / 100 g). Para el radical DPPH, el valor IC50 del tumbo de la región Arequipa (Yunga) fue 0,41 ± 0,01 mg / mL. El tumbo de la región Cusco (Quechua) mostró el valor FRAP más alto (8,38 ± 0,32 mmol Fe2 + / 100 g). El cerezo de la región de Arequipa (Yunga) presentó la mayor concentración de fenoles totales (181,81 ± 34,1 mg EAG / 100 g) y flavonoides (205,18 ± 77,8 mg EQ / 100 g). El cerezo de Arequipa (Yunga) mostró una actividad antioxidante significativa al DPPH (2,1 ± 0,01 mg / mL), mientras que la capacidad antioxidante del cerezo de la región Cusco (Quechua), evaluada con la técnica FRAP, alcanzó un valor de 1,59 ± 0,2 mmol Fe2+/100 g. Las diferencias observadas fueron estadísticamente significativas. El tumbo mostró un mejor efecto hepatoprotector que el cerezo. Conclusiones: El tumbo de la región Cusco (Quechua) es una fuente importante de compuestos antioxidantes y muestra una elevada capacidad antioxidante (FRAP), mientras que el cerezo de la región Arequipa (Yunga) tiene un alto contenido de compuestos antioxidantes y una mayor capacidad antioxidante (DPPH).

Objective: To determine the content of bioactive compounds and antioxidant capacity of the banana passionfruit (Passiflora mollissima) and black cherry (Prunus serotina). Materials and methods: An analytical, experimental, longitudinal and prospective study. The black cherries and banana passionfruits were collected in the Cusco, Moquegua and Arequipa regions. The content of phenols and flavonoids were determined using the Folin-Ciocalteu reagent and aluminum chloride method, respectively. The antioxidant activity was evaluated using the ferric reducing ability of plasma (FRAP), 2,2-diphenyl-1-picryl-hydrazyl (DPPH) and thiobarbituric acid reactive substance (TBARS) techniques. Albino rats classified into a negative control group, a positive control group and four experimental groups were used to study the hepatoprotective effect of the fruits. Results: Banana passionfruits from the Cusco region (Quechua) showed the highest concentration of total phenols (584.94 ± 134.62 mg GAE/100 g) and flavonoids (445.62 ± 7.94 mg QE/100 g). Concerning the DPPH radical, the IC 50 value of banana passionfruits from the Arequipa region (Yunga) was found to be 0.41 ± 0.01 mg/mL. Banana passionfruits from the Cusco region (Quechua) showed the highest FRAP value (8.38 ± 0.32 mmol Fe2+/100 g). Black cherries from the Arequipa region (Yunga) had the highest concentration of total phenols (181.81 ± 34.1 mg GAE/100 g) and flavonoids (205.18 ± 77.8 mg QE/100 g). They also showed a significant antioxidant activity regarding the DPPH (2.1 ± 0.01 mg/mL), while the antioxidant capacity of black cherries from the Cusco region (Quechua), which was evaluated with the FRAP method, achieved a value of 1.59 ± 0.2 mmol Fe2+/100 g. The observed differences were statistically significant. Banana passionfruits showed a better hepatoprotective effect than black cherries. Conclusions: Banana passionfruits from the Cusco region (Quechua) are an important source of antioxidant compounds and show a high antioxidant capacity (FRAP), while black cherries from the Arequipa region (Yunga) have a high content of antioxidant compounds and a higher antioxidant capacity (DPPH).

Disgerminoma en el Hospital Regional Honorio Delgado de Arequipa / Dysgerminoma in the Hospital Regional Honorio Delgado de Arequipa

Se realiza un estudio de nueve casos de disgerminoma registrados en el Servicio de Ginecología del Hospital Regional Honorio Deldado (Arequipa-Perú), entre 1960 y 1986. Los disgerminomas son tumores relativamente raros, corresponden alrededor del 1 por ciento de las neoplasias ováricas. En nuestra serie constituyó el 0.32 por ciento de tumores de ovario primarios, y el 13.24 por ciento de las malignas. Se demuestra una mayor incidencia entre la segunda y tercera década de la vida. No se encontró alteración significativa con la menarquía; el régimen catamenial conservó su regularidad. La presencia de tumoración y dolor abdominal son hechos constantes y deben de orientar hacia la presunción diagnóstica de esta patología. Hubo asociación con embarazo en dos pacientes. En la mayoría de los casos el tratamiento quirúrgico fue conservador. Se discute los hallazgos clínico-patológicos dentro del contexto de publicaciones similares, deduciéndose que es difícil precisar el diagnóstico, debido a que las manifestaciones clínicas de los disgerminomas habitualmente son similares a las producidas por otro tipo de tumoraciones pélvico-abdominales