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001-es BibID:	BIBFORM103422
035-os BibID:	(cikkazonosító)2633 (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:	BIBFORM103424
035-os BibID:	(WOS)000837443600001 (Scopus)85134360196
Első szerző:	Jdeed, Sham
Cím:	The Role of ARID1A in the Nonestrogenic Modulation of IGF-1 Signaling / Jdeed Sham, Erdős Edina, Bálint Bálint L., Uray Iván P.
Dátum:	2022
ISSN:	1541-7786
Megjegyzések:	Gaining pharmacologic access to the potential of ARID1A, a tumor suppressor protein, to mediate transcriptional control over cancer gene expression is an unresolved challenge. Retinoid X receptor ligands are pleiotropic, incompletely understood tools that regulate breast epithelial cell proliferation and differentiation. We found that low-dose bexarotene (Bex) combined with the nonselective beta-blocker carvedilol (Carv) reduces proliferation of MCF10DCIS.com cells and markedly suppresses ARID1A levels. Similarly, Carv synergized with Bex in MCF-7 cells to suppress cell growth. Chromatin immunoprecipitation sequencing analysis revealed that under nonestrogenic conditions Bex ? Carv alters the concerted genomic distribution of the chromatin remodeler ARID1A and acetylated histone H3K27, at sites related to insulinlike growth factor (IGF) signaling. Several distinct sites of ARID1A enrichment were identified in the IGF-1 receptor and IRS1 genes, associated with a suppression of both proteins. The knock-down of ARID1A increased IGF-1R levels, prevented IGF-1R and IRS1 suppression upon Bex ? Carv, and stimulated proliferation. In vitro IGF-1 receptor neutralizing antibody suppressed cell growth, while elevated IGF-1R or IRS1 expression was associated with poor survival of patients with ER-negative breast cancer. Our study demonstrates direct impact of ARID1A redistribution on the expression and growth regulation of IGF-1? related genes, induced by repurposed clinical drugs under nonestrogenic conditions.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk ARID1A IGF-I rexinoid growth suppression
Megjelenés:	Molecular Cancer Research. - 20 : 7 (2022), p. 1071-1082. -
További szerzők:	Erdős Edina (1989-) (klinikai laboratóriumi kutató) Bálint Bálint László (1971-) (kutató orvos) Uray Iván Péter (1970-) (kutatóorvos)
Pályázati támogatás:	NKFIH-K129218 OTKA GINOP-2.3.2-15-2016-00020 GINOP EFOP-3.6.1-16-2016-00022 EFOP
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
Borító:
Saját polcon: