The microphthalmia-associated transcription factor (MITF) is required for melanocyte development, maintenance of the melanocyte-specific transcription, and survival of melanoma cells. MITF positively regulates expression of more than 25 genes in pigment cells. Recently, it has been demonstrated that expression of several MITF downstream targets requires the SWI/SNF chromatin remodeling complex, which contains one of the two catalytic subunits, Brm or Brg1. Here we show that the expression of MITF itself critically requires active SWI/SNF. In several Brm/Brg1-expressing melanoma cell lines, knockdown of Brg1 severely compromised MITF expression with a concomitant downregulation of MITF targets and decreased cell proliferation. Although Brm was able to substitute for Brg1 in maintaining MITF expression and melanoma cell proliferation, sequential knockdown of both Brm and Brg1 in 501mel cells abolished proliferation. In Brg1-null SK-MEL-5 melanoma cells, depletion of Brm alone was sufficient to abrogate MITF expression and cell proliferation. Chromatin immunoprecipitation confirmed the binding of Brg1 or Brm to the promoter of MITF. Together these results demonstrate the essential role of SWI/SNF for expression of MITF and suggest that SWI/SNF may be a promissing target in melanoma therapy.

• MeSH
• aktivace transkripce * MeSH
• chromozomální proteiny, nehistonové metabolismus   MeSH
• DNA-helikasy metabolismus   MeSH
• imunoprecipitace MeSH
• jaderné proteiny metabolismus   MeSH
• lidé MeSH
• melanom genetika   MeSH
• nádorové buněčné linie MeSH
• promotorové oblasti (genetika) MeSH
• regulace genové exprese u nádorů * MeSH
• restrukturace chromatinu * MeSH
• transkripční faktor spojený s mikroftalmií genetika   MeSH
• transkripční faktory metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chromozomální proteiny, nehistonové MeSH
• DNA-helikasy MeSH
• jaderné proteiny MeSH
• MITF protein, human MeSH Prohlížeč
• SMARCA2 protein, human MeSH Prohlížeč
• SMARCA4 protein, human MeSH Prohlížeč
• SWI-SNF-B chromatin-remodeling complex MeSH Prohlížeč
• transkripční faktor spojený s mikroftalmií MeSH
• transkripční faktory MeSH

Chromatin structure and its changes or maintenance throughout developmental checkpoints play indispensable role in organismal homeostasis. Chromatin remodeling factors of the SWI/SNF2 superfamily use ATP hydrolysis to change DNA-protein contacts, and their loss-of-function or inappropriate increase leads to distinct human pathologic states. In this review, we focus on the translational view of human pathologic physiology involving SWI/SNF2 superfamily, combining latest finding from basic and clinical research. We discuss in mechanistic terms the consequences resulting from dose alteration of the SWI/SNF2 superfamily ATPases and emphasize the necessity of future human subject-based studies.

• MeSH
• chromatin metabolismus   MeSH
• chromozomální proteiny, nehistonové metabolismus   MeSH
• DNA nádorová metabolismus   MeSH
• DNA-helikasy genetika   metabolismus   MeSH
• DNA metabolismus   MeSH
• genetické nemoci vrozené genetika   metabolismus   MeSH
• histony metabolismus   MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• leukemie genetika   metabolismus   MeSH
• lidé MeSH
• nádory genetika   metabolismus   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• BAZ1B protein, human MeSH Prohlížeč
• chromatin MeSH
• chromozomální proteiny, nehistonové MeSH
• DNA nádorová MeSH
• DNA-helikasy MeSH
• DNA MeSH
• histony MeSH
• jaderné proteiny MeSH
• SMARCA4 protein, human MeSH Prohlížeč
• SWI-SNF-B chromatin-remodeling complex MeSH Prohlížeč
• transkripční faktory MeSH

Several cancer core regulatory circuitries (CRCs) depend on the sustained generation of DNA accessibility by SWI/SNF chromatin remodelers. However, the window when SWI/SNF is acutely essential in these settings has not been identified. Here we used neuroblastoma (NB) cells to model and dissect the relationship between cell-cycle progression and SWI/SNF ATPase activity. We find that SWI/SNF inactivation impairs coordinated occupancy of non-pioneer CRC members at enhancers within 1 hour, rapidly breaking their autoregulation. By precisely timing inhibitor treatment following synchronization, we show that SWI/SNF is dispensable for survival in S and G2/M, but becomes acutely essential only during G1 phase. We furthermore developed a new approach to analyze the oscillating patterns of genome-wide DNA accessibility across the cell cycle, which revealed that SWI/SNF-dependent CRC binding sites are enriched at enhancers with peak accessibility during G1 phase, where they activate genes involved in cell-cycle progression. SWI/SNF inhibition strongly impairs G1-S transition and potentiates the ability of retinoids used clinically to induce cell-cycle exit. Similar cell-cycle effects in diverse SWI/SNF-addicted settings highlight G1-S transition as a common cause of SWI/SNF dependency. Our results illustrate that deeper knowledge of the temporal patterns of enhancer-related dependencies may aid the rational targeting of addicted cancers.

Cancer cells driven by runaway transcription factor networks frequently depend on the cellular machinery that promotes DNA accessibility. For this reason, recently developed small molecules that impair SWI/SNF (or BAF) chromatin remodeling activity have been under active evaluation as anti-cancer agents. However, exactly when SWI/SNF activity is essential in dependent cancers has remained unknown. By combining live-cell imaging and genome-wide profiling in neuroblastoma cells, Cermakova et al. discover that SWI/SNF activity is needed for survival only during G1 phase of the cell cycle. The authors reveal that in several cancer settings, dependency on SWI/SNF arises from the need to reactivate factors involved in G1-S transition. Because of this role, authors find that SWI/SNF inhibition potentiates cell-cycle exit by retinoic acid.

• MeSH
• buněčný cyklus MeSH
• chromatin genetika   MeSH
• DNA MeSH
• G1 fáze * MeSH
• lidé MeSH
• nádory * MeSH
• regulační oblasti nukleových kyselin MeSH
• restrukturace chromatinu MeSH
• transkripční faktory * metabolismus   MeSH
• zesilovače transkripce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chromatin MeSH
• DNA MeSH
• SWI-SNF-B chromatin-remodeling complex MeSH Prohlížeč
• transkripční faktory * MeSH

Rhabdoid tumors are rare but highly aggressive malignancies of infancy and early childhood with a generally unfavorable prognosis. Despite a wide variety of anatomic locations rhabdoid tumors share mutational inactivation of the SWI/SNF (SWItch/Sucrose NonFermentable) core component gene SMARCB1 (also known as INI1, hSNF5 or BAF47) in chromosome 22. As this inactivation usually results in loss of SMARCB1 expression, detectable by an antibody against the SMARCB1 protein, the accurate diagnosis of a rhabdoid tumor may be more distinctly and frequently made. Several reports on rhabdoid tumors presenting in various anatomic sites outside the kidneys and CNS are on record. We report two cases of rhabdoid tumors originating in the heart (cardiac tissue), which were entered into the European Rhabdoid Registry (EU-RHAB). The first case presented with intracardial and -cranial lesions as well as malignant ascites, while the second patient demonstrated an isolated cardiac tumor. This induced a different therapeutic approach and subsequently different clinical course (death 7 weeks after diagnosis in patient 1). Patient 2 presented with a bifocal intracardial tumor without metastases and remains in complete remission for 46 months since diagnosis following multimodal therapy. The second case demonstrates that even in a potentially futile clinical situation early and accurate diagnosis followed by prompt and intensive multimodal therapy may offer prolonged survival, potential cure and improved quality of life.

• Klíčová slova
• EU-RHAB, Rhabdoid tumor, SMARCB1, heart, intensive multimodal therapy,
• MeSH
• antitumorózní látky terapeutické užití   MeSH
• chromozomální proteiny, nehistonové biosyntéza   genetika   MeSH
• DNA vazebné proteiny biosyntéza   genetika   MeSH
• gen SMARCB1 MeSH
• kojenec MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• metastázy nádorů MeSH
• mutace MeSH
• nádorové supresorové proteiny genetika   MeSH
• nádory srdce genetika   patologie   terapie   MeSH
• registrace MeSH
• rhabdoidní nádor genetika   patologie   terapie   MeSH
• transkripční faktory biosyntéza   genetika   MeSH
• transplantace periferních kmenových buněk * MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• chromozomální proteiny, nehistonové MeSH
• DNA vazebné proteiny MeSH
• gen SMARCB1 MeSH
• nádorové supresorové proteiny MeSH
• SMARCB1 protein, human MeSH Prohlížeč
• SWI-SNF-B chromatin-remodeling complex MeSH Prohlížeč
• transkripční faktory MeSH

Undifferentiated gastrointestinal tract carcinomas are rare highly aggressive neoplasms with frequent but not obligatory rhabdoid features. Recent studies showed loss of SMARCB1 (INI1), a core subunit of the SWI/SNF chromatin remodeling complex, in 50% of tested cases. However, the molecular pathways underlying histologically similar but SMARCB1-intact cases are unknown. We herein analyzed 13 cases for expression of 4 SWI/SNF complex subunits SMARCB1, SMARCA2, SMARCA4, and ARID1A and the mismatch-repair proteins MLH1, MSH2, MSH6, and PMS2 by immunohistochemistry. Patients included 12 men and 1 woman aged 32 to 81 years (median, 57 y). Site of origin was colon (5), small bowel (2), stomach (3), small+large intestine (1), small intestine+ampulla of Vater (1), and esophagogastric junction (1). All tumors showed anaplastic large to medium-sized cells with variable rhabdoid features, pleomorphic giant cells, and, rarely, spindle cell foci. Abortive gland formation was seen in 3 cases and bona fide glandular component in 1 case. Most cases strongly expressed vimentin and variably pancytokeratin. In total, 12/13 cases (92%) showed loss of at least 1 SWI/SNF component. Loss of SMARCB1 (5/13), SMARCA2 (10/13), SMARCA4 (2/13), and ARID1A (2/13) was observed either in combination or isolated. SMARCA2 loss was isolated in 5 cases and coexisted with lost SMARCB1 in 5 cases (all 5 SMARCB1-deficient tumors showed loss of SMARCA2 as well). Co-inactivation of SMARCB1 and SMARCA4 or of SMARCA2 and SMARCA4 was not observed. Two mismatch-repair-deficient cases (MLH1/PMS2) showed concurrent loss of SMARCB1, SMARCA2, and (one of them) ARID1A. This study illustrates for the first time loss of different components of the SWI/SNF complex other than SMARCB1 in undifferentiated gastrointestinal carcinomas including novel SMARCA4-deficient and SMARCA2-deficient cases. Our results underline the close link between SWI/SNF deficiency and the aggressive rhabdoid phenotype. Frequent loss of SMARCA2 possibly points to fragility/vulnerability of the SWI/SNF complex as a consequence of lost core subunit SMARCB1. The exact molecular mechanisms underlying co-inactivation of different SWI/SNF subunits merit further investigations.

• MeSH
• chromozomální proteiny, nehistonové genetika   MeSH
• dědičné nádorové syndromy MeSH
• DNA-helikasy genetika   MeSH
• dospělí MeSH
• gastrointestinální nádory genetika   patologie   MeSH
• imunohistochemie MeSH
• jaderné proteiny genetika   MeSH
• karcinom genetika   patologie   MeSH
• kolorektální nádory MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory mozku MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chromozomální proteiny, nehistonové MeSH
• DNA-helikasy MeSH
• jaderné proteiny MeSH
• SMARCA2 protein, human MeSH Prohlížeč
• SMARCA4 protein, human MeSH Prohlížeč
• SWI-SNF-B chromatin-remodeling complex MeSH Prohlížeč
• transkripční faktory MeSH

Metastasized malignant melanoma has a poor prognosis because of its intrinsic resistance to chemotherapy and radiotherapy. The central role in the melanoma transcriptional network has the transcription factor MITF (microphthalmia-associated transcription factor). It has been shown recently that the expression of MITF and some of its target genes require the SWI/SNF chromatin remodeling complex. Here we demonstrate that survival of melanoma cells requires functional SWI/SNF complex not only by supporting expression of MITF and its targets and but also by activating expression of prosurvival proteins not directly regulated by MITF. Microarray analysis revealed that besides the MITF-driven genes, expression of proteins like osteopontin, IGF1, TGFß2 and survivin, the factors known to be generally associated with progression of tumors and the antiapoptotic properties, were reduced in acute BRG1-depleted 501mel cells. Western blots and RT-PCR confirmed the microarray findings. These proteins have been verified to be expressed independently of MITF, because MITF depletion did not impair their expression. Because these genes are not regulated by MITF, the data suggests that loss of BRG1-based SWI/SNF complexes negatively affects survival pathways beyond the MITF cascade. Immunohistochemistry showed high expression of both BRM and BRG1 in primary melanomas. Exogenous CDK2, osteopontin, or IGF1 each alone partly relieved the block of proliferation imposed by BRG1 depletion, implicating that more factors, besides the MITF target genes, are involved in melanoma cell survival. Together these results demonstrate an essential role of SWI/SNF for the expression of MITF-dependent and MITF-independent prosurvival factors in melanoma cells and suggest that SWI/SNF may be a potential and effective target in melanoma therapy.

• MeSH
• apoptóza genetika   MeSH
• chromozomální proteiny, nehistonové genetika   metabolismus   MeSH
• cyklin-dependentní kinasa 2 genetika   metabolismus   MeSH
• DNA-helikasy genetika   metabolismus   MeSH
• imunohistochemie MeSH
• inhibitory apoptózy genetika   metabolismus   MeSH
• insulinu podobný růstový faktor I genetika   metabolismus   MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• lidé MeSH
• melanom genetika   metabolismus   patologie   MeSH
• nádorové buněčné linie MeSH
• névus genetika   metabolismus   patologie   MeSH
• osteopontin genetika   metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• proliferace buněk MeSH
• RNA interference MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• stanovení celkové genové exprese MeSH
• survivin MeSH
• transformující růstový faktor beta2 genetika   metabolismus   MeSH
• transkripční faktor spojený s mikroftalmií genetika   metabolismus   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• viabilita buněk genetika   MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• BIRC5 protein, human MeSH Prohlížeč
• CDK2 protein, human MeSH Prohlížeč
• chromozomální proteiny, nehistonové MeSH
• cyklin-dependentní kinasa 2 MeSH
• DNA-helikasy MeSH
• inhibitory apoptózy MeSH
• insulinu podobný růstový faktor I MeSH
• jaderné proteiny MeSH
• MITF protein, human MeSH Prohlížeč
• osteopontin MeSH
• SMARCA2 protein, human MeSH Prohlížeč
• SMARCA4 protein, human MeSH Prohlížeč
• survivin MeSH
• SWI-SNF-B chromatin-remodeling complex MeSH Prohlížeč
• transformující růstový faktor beta2 MeSH
• transkripční faktor spojený s mikroftalmií MeSH
• transkripční faktory MeSH

Loss of the SWI/SNF chromatin remodeling complex has been recently implicated in the pathogenesis of dedifferentiated carcinomas from different organs, but its possible role in undifferentiated urothelial carcinoma (UC) has not been studied to date. In this study, we analyzed by immunohistochemistry 14 undifferentiated UCs (11 from bladder and 3 from renal pelvis) with a nondescript anaplastic or rhabdoid morphology, using commercially available antibodies against the SWI/SNF components SMARCB1 (INI1), SMARCA2, SMARCA4, SMARCC1, SMARCC2, and ARID1A. Patients were eight females and six males aged 40 to 84 years (median, 65). All tumors were muscle-invasive (9 were T3-4). A conventional UC component was seen in eight cases and varied from in situ to papillary. The undifferentiated component comprised 60-100 % of the tumors. Histologically, most tumors showed diffuse dyscohesive or pseudoalveolar growth of variably sized cells with frequent rhabdoid features. Transition from conventional to undifferentiated UC was abrupt, except in one case. The undifferentiated component almost always expressed pan-cytokeratin AE1/AE3 (13/14) and variably vimentin (8/14) and GATA3 (9/14). Complete loss of at least one SWI/SNF subunit limited to the undifferentiated component was detected in 10/14 cases (71 %). SMARCA2 was most frequently lost (six) followed by ARID1A (four), SMARCB1/INI1 (two), SMARCA4 (one), and SMARCC1 (one). This is the first study exploring SWI/SNF expression in undifferentiated UC of the urinary tract. Our results are in line with recent studies reporting involvement of the SWI/SNF complex in the dedifferentiation process of a variety of epithelial neoplasms in different organs, including the urinary tract, and association with aggressive clinical course.

• Klíčová slova
• ARID1A, Renal pelvis, Rhabdoid carcinoma, SMARCA2, SMARCB1, SWI/SNF, Undifferentiated carcinoma, Urinary bladder, Urothelial carcinoma,
• MeSH
• DNA vazebné proteiny MeSH
• DNA-helikasy metabolismus   MeSH
• dospělí MeSH
• gen SMARCB1 metabolismus   MeSH
• imunohistochemie metody   MeSH
• jaderné proteiny metabolismus   MeSH
• karcinom z přechodných buněk metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• močové ústrojí metabolismus   patologie   MeSH
• rhabdoidní nádor diagnóza   metabolismus   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transkripční faktory metabolismus   MeSH
• urologické nádory diagnóza   metabolismus   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ARID1A protein, human MeSH Prohlížeč
• DNA vazebné proteiny MeSH
• DNA-helikasy MeSH
• gen SMARCB1 MeSH
• jaderné proteiny MeSH
• SMARCA2 protein, human MeSH Prohlížeč
• SMARCA4 protein, human MeSH Prohlížeč
• SMARCB1 protein, human MeSH Prohlížeč
• SMARCC1 protein, human MeSH Prohlížeč
• transkripční faktory MeSH

UNLABELLED: In acute myeloid leukemia (AML), SWI/SNF chromatin remodeling complexes sustain leukemic identity by driving high levels of MYC. Previous studies have implicated the hematopoietic transcription factor PU.1 (SPI1) as an important target of SWI/SNF inhibition, but PU.1 is widely regarded to have pioneer-like activity. As a result, many questions have remained regarding the interplay between PU.1 and SWI/SNF in AML as well as normal hematopoiesis. Here we found that PU.1 binds to most of its targets in a SWI/SNF-independent manner and recruits SWI/SNF to promote accessibility for other AML core regulatory factors, including RUNX1, LMO2, and MEIS1. SWI/SNF inhibition in AML cells reduced DNA accessibility and binding of these factors at PU.1 sites and redistributed PU.1 to promoters. Analysis of nontumor hematopoietic cells revealed that similar effects also impair PU.1-dependent B-cell and monocyte populations. Nevertheless, SWI/SNF inhibition induced profound therapeutic response in an immunocompetent AML mouse model as well as in primary human AML samples. In vivo, SWI/SNF inhibition promoted leukemic differentiation and reduced the leukemic stem cell burden in bone marrow but also induced leukopenia. These results reveal a variable therapeutic window for SWI/SNF blockade in AML and highlight important off-tumor effects of such therapies in immunocompetent settings. SIGNIFICANCE: Disruption of PU.1-directed enhancer programs upon SWI/SNF inhibition causes differentiation of AML cells and induces leukopenia of PU.1-dependent B cells and monocytes, revealing the on- and off-tumor effects of SWI/SNF blockade.

• MeSH
• akutní myeloidní leukemie * farmakoterapie   genetika   metabolismus   MeSH
• buněčná diferenciace MeSH
• kostní dřeň patologie   MeSH
• leukopenie * genetika   MeSH
• lidé MeSH
• myši MeSH
• promotorové oblasti (genetika) MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Since the first description of sinonasal undifferentiated carcinoma (SNUC) as a distinctive highly aggressive sinonasal neoplasm with probable origin from the sinonasal mucosa (Schneiderian epithelium), SNUC has been the subject of ongoing study and controversy. In particular, the SNUC category gradually became a "wastebasket" for any undifferentiated or unclassifiable sinonasal malignancy of definite or probable epithelial origin. However, with the availability of more specific and sensitive immunohistochemical antibodies and increasing implementation of novel genetic tools, the historical SNUC category became the subject of progressive subdivision leading to recognition of specific genetically defined, reproducible subtypes. These recently recognized entities are characterized by distinctive genetic aberrations including NUTM1-rearranged carcinoma (NUT carcinoma) and carcinomas associated with inactivation of different members of the SWI/SNF chromatin-remodeling gene complex such as SMARCB1-deficient and less frequently SMARCA4-deficient carcinoma. The ring became almost closed, with recent studies highlighting frequent oncogenic IDH2 mutations in the vast majority of histologically defined SNUCs, with a frequency of 82%. A review of these cases suggests the possibility that "true SNUC" probably represents a distinctive neoplastic disease entity, morphologically, phenotypically, and genetically. This review addresses this topic from a historical perspective, with a focus on recently recognized genetically defined subsets within the SNUC spectrum.

• MeSH
• DNA-helikasy genetika   MeSH
• gen SMARCB1 genetika   MeSH
• jaderné proteiny genetika   MeSH
• karcinom diagnóza   epidemiologie   genetika   MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory sinu maxillaris diagnóza   epidemiologie   genetika   MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• DNA-helikasy MeSH
• gen SMARCB1 MeSH
• jaderné proteiny MeSH
• nádorové biomarkery MeSH
• SMARCA4 protein, human MeSH Prohlížeč
• SMARCB1 protein, human MeSH Prohlížeč
• transkripční faktory MeSH