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Targeting the novel SALL4/CBL-B pathway by HDAC inhibitor MS-275 in lung cancer

ABSTRACT: The overall survival of lung cancer patients remains dismal despite the availability of targeted therapies. Oncofetal protein SALL4 is a novel cancer target. We herein report that SALL4 was aberrantly expressed in a subset of lung cancer patients with poor survival. SALL4 silencing by RNA interference or SALL4 peptide inhibitor treatment led to impaired lung cancer cell growth. Expression profiling on SALL4-knockdown cells demonstrated that both the EGFR and IGF1R signaling pathways were affected. Further studies revealed that SALL4 suppresses these pathways indirectly by repressing CBL-B. Connectivity Map analysis revealed HDAC inhibitor MS-275 as a potential drug in treating SALL4-expressing cancers and this was confirmed using 17 lung cancer cell lines. In summary, we report for the first time that MS-275 can target the novel SALL4/CBL-B pathway in lung cancer. This lays the foundation for future clinical studies to evaluate the therapeutic efficacy of MS-275 in SALL4-positive lung cancer patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE68959 | GEO | 2015/05/16

SECONDARY ACCESSION(S): PRJNA284164

REPOSITORIES: GEO

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Targeting the novel SALL4/CBL-B pathway by HDAC inhibitor MS-275 in lung cancer

Project description:The overall survival of lung cancer patients remains dismal despite the availability of targeted therapies. Oncofetal protein SALL4 is a novel cancer target. We herein report that SALL4 was aberrantly expressed in a subset of lung cancer patients with poor survival. SALL4 silencing by RNA interference or SALL4 peptide inhibitor treatment led to impaired lung cancer cell growth. Expression profiling on SALL4-knockdown cells demonstrated that both the EGFR and IGF1R signaling pathways were affected. Further studies revealed that SALL4 suppresses these pathways indirectly by repressing CBL-B. Connectivity Map analysis revealed HDAC inhibitor MS-275 as a potential drug in treating SALL4-expressing cancers and this was confirmed using 17 lung cancer cell lines. In summary, we report for the first time that MS-275 can target the novel SALL4/CBL-B pathway in lung cancer. This lays the foundation for future clinical studies to evaluate the therapeutic efficacy of MS-275 in SALL4-positive lung cancer patients. Cells from human lung carcinoma cell line H661 with wildtype scrambled controls or Sall4 knockdown were used for RNA extraction and hybridization on Affymetrix microarrays.

2015-05-16 | E-GEOD-68959 | biostudies-arrayexpress

Homo sapiens

Project description:Targeting the novel SALL4/CBL-B pathway by HDAC inhibitor MS-275 in lung cancer

| PRJNA284164 | ENA

MS-275 and Isotretinoin in Treating Patients With Metastatic or Advanced Solid Tumors or Lymphomas

Project description:Phase I trial to study the effectiveness of combining MS-275 with isotretinoin in treating patients who have metastatic or advanced solid tumors or lymphomas. MS-275 may stop the growth of cancer cells by blocking the enzymes necessary for their growth. Isotretinoin may help cancer cells develop into normal cells. MS-275 may increase the effectiveness of isotretinoin by making cancer cells more sensitive to the drug. MS-275 and isotretinoin may also stop the growth of solid tumors or lymphomas by stopping blood flow to the cancer. Combining MS-275 with isotretinoin may kill more cancer cells

| 2011932 | ecrin-mdr-crc

MS-275 in Treating Patients With Advanced Solid Tumors or Lymphoma

Project description:RATIONALE: MS-275 may stop the growth of cancer cells by blocking the enzymes necessary for their growth. PURPOSE: This phase I trial is studying the side effects and best dose of MS-275 in treating patients with advanced solid tumors or lymphoma.

| 2006457 | ecrin-mdr-crc

Expression profiling of 275 lung cancer specimens

Project description:From ~1,700 non-small cell lung cancer specimens collected at the MD Anderson Cancer Center over the years 1997 to 2005, we selected 914 tumors with detailed clinical and pathological information. We extracted RNA and DNA from frozen tissues using histology quality control from 700 cases. RNA was examined for quality using Agilent Bioanalyzer and RNA integrity number (RIN) was obtained for all specimens. A final selection of 275 tumor specimens was based on the following criteria: 1) Select mainly adenocarcinomas (n = 183) and squamous carcinomas (n = 80); 2) Tissue material contains at least 70% tumor by section examination; 3) within the tumor section, there should be at least 30% tumor cells (as opposed to stromal cells); 4) RIN should be at least 4.0 (range 0 - 10). Various profiling experiments were then performed including mRNA expression (this study), miRNA profiling, aCGH (Agilent), Reverse-phase protein array (RPPA), mutation analysis of 20 genes (Sequenom) and MS-MALDI-TOFF analysis. 275 lung cancer specimens collected at the MD Anderson Cancer Center were profiled on Illumina WG6-V3 expression arrays. Detailed clinico-pathological information were also collected.

2013-07-01 | E-GEOD-41271 | biostudies-arrayexpress

Transcriptome analysis of mouse embryonic stem cells treated with MS-275

Project description:This study describes transcriptome profiling of mouse ES cells treated with MS-275. We included RNA-Seq of ds_cDNA synthesized from double poly(A) selected mRNA RNA-Seq profiling on mouse ES cells treated with MS-275

2014-03-28 | E-GEOD-45909 | biostudies-arrayexpress

Inhibition of histone deacetylation by MS-275 alleviates colitis by activating the vitamin D receptor

Project description:BACKGROUND: Ulcerative colitis (UC) is a common chronic inflammatory bowel disease without curative treatment. METHODS: We conducted gene set enrichment analysis to explore potential therapeutic agent for UC. Human colon tissue samples were collected to test H3 acetylation in UC. Both in vivo and in vitro colitis models were constructed to verify the role and mechanism of H3 acetylation modification in UC. Intestine-specific vitamin D receptor (VDR)-/- mice and VD (vitamin D)-deficient diet-fed mice were used to explore downstream molecular mechanism accordingly. RESULTS: According to the Connectivity Map database, MS-275 (class I histone deacetylase inhibitor) was the top-ranked agent, indicating potential importance of histone acetylation in the pathogenesis of UC. We then found that histone H3 acetylation was significantly decreased in the colon epithelium of UC patients and negatively associated with disease severity. MS-275 treatment inhibited histone H3 deacetylation, and subsequently attenuated nuclear factor kappa B (NF-?B)-induced inflammation, reduced cellular apoptosis, maintained epithelial barrier function, and thereby reduced colitis activity in a mouse model of colitis. We also identified VDR to be a downstream effector of MS-275. The curative effect of MS-275 on colitis was abolished in VDR-/- mice and in VD-deficient diet-fed mice and VDR directly targeted p65. In UC patients, histone H3 acetylation, VDR and zonulin-1 expression showed similar downregulation patterns and were negatively associated with disease severity. CONCLUSION: We demonstrate that MS-275 inhibits histone deacetylation and alleviates colitis by ameliorating inflammation, reducing apoptosis and maintaining intestinal epithelial barrier via VDR, providing new strategies for UC treatment.

2020-09-23 | GSE138495 | GEO

Significance of SALL4 as a drug resistant factor in lung cancer

2014-04-30 | GSE56595 | GEO

Significance of SALL4 as a drug resistant factor in lung cancer

Project description:To examine the mechanism by which SALL4 regulates drug sensitivity, approximately 65,000 molecules on a microarray chip were analyzed using lung cancer cells transduced with a SALL4 vector (pCMV6-SALL4) or a control vector (pCMV6-Mock) . SALL4 mRNA and protein expression markedly increased after 24 hr of SALL4 vector transduction, unlike that in the cells transduced with the control vector; these cells were used for microarray analysis.

2014-04-30 | E-GEOD-56595 | biostudies-arrayexpress

Next-Generation Sequencing Supports Quantitative Analysis of Wild Type and Runx2+/- Calvarial Transcriptomes With or Without Administration of MS-275

Project description:Because insufficiency of the Runt-related transcription factor 2 (Runx2) limits skeletal growth, there is a great deal of effort to activate Runx2 for clinical use. In this study, we found that MS-275, the class I-specific HDAC inhibitor, activates Runx2 both transcriptionally and translationally. Therefore, we performed NGS analysis to gain accurate patterns of gene expression in mouse calvaria tissue through MS-275 administration. As a result, we could get insight that treatment of MS-275 increases genes related with osteoblast differentiation and cell proliferation, and decreases genes in field of causing apoptosis.

2017-09-24 | GSE87608 | GEO

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