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001-es BibID:	BIBFORM103422
035-os BibID:	(WOS)000852874400001 (Scopus)85137545921
Első szerző:	Jdeed, Sham
Cím:	Redistribution of the SWI/SNF Complex Dictates Coordinated Transcriptional Control over Epithelial-Mesenchymal Transition of Normal Breast Cells through TGF-[béta] Signaling / Jdeed Sham, Lengyel Máté, Uray Iván P.
Dátum:	2022
ISSN:	2073-4409
Megjegyzések:	Therapeutic targets in cancer cells defective for the tumor suppressor ARID1A are fundamentals of synthetic lethal strategies. However, whether modulating ARID1A function in premalignant breast epithelial cells could be exploited to reduce carcinogenic potential remains to be elucidated. In search of chromatin-modulating mechanisms activated by anti-proliferative agents in normal breast epithelial (HME-hTert) cells, we identified a distinct pattern of genome-wide H3K27 histone acetylation marks characteristic for the combined treatment by the cancer preventive rexinoid bexarotene (Bex) and carvedilol (Carv). Among these marks, several enhancers functionally linked to TGF- b signaling were enriched for ARID1A and Brg1, subunits within the SWI/SNF chromatin remodeling complex. The recruitment of ARID1A and Brg1 was associated with the suppression of TGFBR2, KLF4, and FoxQ1, and the induction of BMP6, while the inverse pattern ensued upon the knock-down of ARID1A. Bex+Carv treatment resulted in fewer cells expressing N-cadherin and dictated a more epithelial phenotype. However, the silencing of ARID1A expression reversed the ability of Bex and Carv to limit epithelial?mesenchymal transition. The nuclear levels of SMAD4, a canonical mediator of TGF- action, were more effectively suppressed by the combination than by TGF- . In contrast, TGF- treatment exceeded the ability of Bex+Carv to lower nuclear FoxQ1 levels and induced markedly higher E-cadherin positivity, indicating a target-selective antagonism of Bex+Carv to TGF- action. In summary, the chromatin-wide redistribution of ARID1A by Bex and Carv treatment is instrumental in the suppression of genes mediating TGF- signaling, and, thus, the morphologic reprogramming of normal breast epithelial cells. The concerted engagement of functionally linked targets using low toxicity clinical agents represents an attractive new approach for cancer interception.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk ARID1A SWI/SNF epithelial-mesenchymal transition TGF-b FoxQ1 bexarotene
Megjelenés:	Cells. - 11 : 17 (2022), p. 1-15. -
További szerzők:	Lengyel Máté Uray Iván Péter (1970-) (kutatóorvos)
Pályázati támogatás:	NKFIH-K129218 OTKA EFOP-3.6.1-16-2016-00022 EFOP GINOP-2.3.2-15-2016-00020 GINOP
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM125352
035-os BibID:	(scopus)85208147130 (wos)001357492000001
Első szerző:	Lengyel Máté
Cím:	Zymogen granule protein 16B (ZG16B) is a druggable epigenetic target to modulate the mammary extracellular matrix / Lengyel Máté, Molnár Ádám, Nagy Tamás, Jdeed Sham, Garai Ildikó, Horváth Zsolt, Uray Iván P.
Dátum:	2025
ISSN:	1347-9032
Megjegyzések:	High tissue density of the mammary gland is considered a pro-tumorigenic factor, hence suppressing the stimuli that induce matrix buildup carries the potential for cancer interception. We found that in non-malignant mammary epithelial cells the combination of the chemopreventive agents bexarotene (Bex) and carvedilol (Carv) suppresses the zymogen granule protein 16B (ZG16B, PAUF) through an interaction of ARID1A with a proximal enhancer. Bex?+?Carv also reduced ZG16B levels in vivo in normal breast tissue and MDA-MB231 tumor xenografts. The relevance of ZG16B is underscored by ongoing clinical trials targeting ZG16B in pancreatic cancers, but its role in breast cancer development is unclear. In immortalized mammary epithelial cells, secreted recombinant ZG16B stimulated mitogenic kinase phosphorylation, detachment and mesenchymal characteristics, and promoted proliferation, motility and clonogenic growth. Highly concerted induction of specific laminin, collagen and integrin isoforms indicated a shift in matrix properties toward increased density and cell-matrix interactions. Exogenous ZG16B alone blocked Bex?+?Carv-mediated control of cell growth and migration, and antagonized Bex?+?Carv-induced gene programs regulating cell adhesion and migration. In breast cancer cells ZG16B induced colony formation and anchorage-independent growth, and stimulated migration in a PI3K/Akt-dependent manner. In contrast, Bex?+?Carv inhibited colony formation, reduced Ki67 levels, ZG16B expression and glucose uptake in MDA-MB231 xenografts. These data establish ZG16B as a druggable pro-tumorigenic target in breast cell transformation and suggest a key role of the matrisome network in rexinoid-dependent antitumor activity.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk
Megjelenés:	Cancer Science. - 116 : 1 (2025), p. 81-94. -
További szerzők:	Molnár Ádám Nagy Tamás (1977-) (vegyész, orvosi laboratóriumi analitikus) Jdeed, Sham (1990-) Garai Ildikó (1966-) (radiológus) Horváth Zsolt (1964-) (onkológus, belgyógyász, klinikai farmakológus) Uray Iván Péter (1970-) (kutatóorvos)
Pályázati támogatás:	OTKA K129218 OTKA GINOP-2.3.2-15-2016-00020 GINOP
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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