<i>SMAR1</i>
            repression by pluripotency factors and consequent chemoresistance in breast cancer stem-like cells is reversed by aspirin

Bhattacharya, Apoorva; Mukherjee, Shravanti; Khan, Poulami; Banerjee, Shruti; Dutta, Apratim; Banerjee, Nilanjan; Sengupta, Dibyendu N.; Basak, Udit; Chakraborty, Sourio; Dutta, Abhishek; Chattopadhyay, Samit; Jana, Kuladip; Sarkar, Diptendra Kumar; Chatterjee, Subhrangsu; Das, Tanya

doi:10.1126/scisignal.aay6077

Cited by 22 publications

(19 citation statements)

References 72 publications

(99 reference statements)

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“…Intriguingly, as mentioned above, asprin decreases the blood levels of several metabolites when cross checked with the human metabolome database. Our results are concordant with multiple reports showing that aspirin can suppress chemoresistance in various malignancies ( 27 – 32 ). A clinical trial is currently evaluating the efficacy of aspirin and tamoxifen in combination with doxorubicin as part of standard AC-T chemotherapy for treatment of high risk ER+ or ER- breast cancer (NCT04038489 clinicaltrials.gov).…”

Section: Discussionsupporting

confidence: 93%

Cellular Metabolomics Profiles Associated With Drug Chemosensitivity in AML

et al. 2021

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BackgroundAcute myeloid leukemia (AML) is a hematological malignancy with a dismal prognosis. For over four decades, AML has primarily been treated by cytarabine combined with an anthracycline. Although a significant proportion of patients achieve remission with this regimen, roughly 40% of children and 70% of adults relapse. Over 90% of patients with resistant or relapsed AML die within 3 years. Thus, relapsed and resistant disease following treatment with standard therapy are the most common clinical failures that occur in treating this disease. In this study, we evaluated the relationship between AML cell line global metabolomes and variation in chemosensitivity.MethodsWe performed global metabolomics on seven AML cell lines with varying chemosensitivity to cytarabine and the anthracycline doxorubicin (MV4.11, KG-1, HL-60, Kasumi-1, AML-193, ME1, THP-1) using ultra-high performance liquid chromatography – mass spectrometry (UHPLC-MS). Univariate and multivariate analyses were performed on the metabolite peak intensity values from UHPLC-MS using MetaboAnalyst to identify cellular metabolites associated with drug chemosensitivity.ResultsA total of 1,624 metabolic features were detected across the leukemic cell lines. Of these, 187 were annotated to known metabolites. With respect to doxorubicin, we observed significantly greater abundance of a carboxylic acid (1-aminocyclopropane-1-carboxylate) and several amino acids in resistant cell lines. Pathway analysis found enrichment of several amino acid biosynthesis and metabolic pathways. For cytarabine resistance, nine annotated metabolites were significantly different in resistance vs. sensitive cell lines, including D-raffinose, guanosine, inosine, guanine, aldopentose, two xenobiotics (allopurinol and 4-hydroxy-L-phenylglycine) and glucosamine/mannosamine. Pathway analysis associated these metabolites with the purine metabolic pathway.ConclusionOverall, our results demonstrate that metabolomics differences contribute toward drug resistance. In addition, it could potentially identify predictive biomarkers for chemosensitivity to various anti-leukemic drugs. Our results provide opportunity to further explore these metabolites in patient samples for association with clinical response.

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Section: Discussionsupporting

confidence: 93%

Cellular Metabolomics Profiles Associated With Drug Chemosensitivity in AML

et al. 2021

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“…In the present study, we showed that knockdown of HDAC2, but not other HDACs, rescue the inhibition of SMAR1 on ABCG2. Additionally, this SMAR1‐HDAC2 interaction is confirmed in breast cancer 15 . Notably, SMAR1 is shown to recruit HDAC5 to the promoter of β‐catenin in colorectal cancer 11 .…”

Section: Discussionmentioning

confidence: 72%

“…Consistently, a recent work shows that SMAR1 suppresses the stemness of breast cancer cells. 15 Therefore, further studies could be constructed to determine whether SMAR1-mediated inhibition on cancer cell stemness is a common phenomenon.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, this SMAR1-HDAC2 interaction is confirmed in breast cancer. 15 Notably, SMAR1 is shown to recruit HDAC5 to the promoter of β-catenin in colorectal cancer. 11 However, these results suggest that SMAR1 might recruit different HDACs to different target genes in different cancers.…”

Section: Discussionmentioning

confidence: 99%

“…These observations suggest that SMAR1 may have an “anti‐CSC” effect. For example, a recent study indicates that SMAR1 represses the CSC‐like traits of breast cancer cells 15 . However, the roles of SMAR1 are never been revealed in OS progression.…”

Section: Introductionmentioning

confidence: 99%

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SMAR1 attenuates the stemness of osteosarcoma cells via through suppressing ABCG2 transcriptional activity

Liu

et al. 2021

Environmental Toxicology

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The promoting roles of the transcriptional regulator SMAR1 have been revealed in several tumors, such as colorectal and breast cancer, however, its roles in osteosarcoma (OS) progression are still confusing. Here, we find that SMAR1 expression is positively correlated with the overall survival of OS patients and negatively correlated with the expression of stemness markers by analyzing the online datasets. Through analyzing different Gene Expression Omnibus (GEO) datasets, SMAR1 is found to be lowly expressed in OS tissues relative to that in adjacent tissues. Functional experiments indicate that SMAR1 overexpression attenuates the stemness of OS cells, characterized as the decrease of stemness marker expression, sphere-formation ability and ALDH activity. Mechanistically, it is shown that SMAR1 increases the deacetylation level of the drug efflux pump ABCG2 via recruiting HDAC2 to the promoter of the gene coding ABCG2, and thus decreases ABCG2 transcriptional activity. Additionally, overexpression of ABCG2 rescues the inhibition of SMAR1 overexpression on the stemness of OS cells. Moreover, this SMAR1/ABCG2 axis positively regulates the chemotherapeutic sensitivity of OS cells. This work indicates that SMAR1 is a critical suppressor for OS progression through transcriptionally regulating ABCG2 expression.

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RING finger protein TOPORS modulates the expression of tumor suppressor SMAR1 in colorectal cancer via the TLR4‐TRIF pathway

et al. 2022

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TOP1‐binding arginine/serine‐rich protein (TOPORS), a really interesting new gene finger protein, has the ability to bind to a palindromic consensus DNA sequence that enables it to function as a potential transcriptional regulator. However, its role in regulating the transcription of cancer‐associated genes is yet to be explored. As Toll‐like receptor 4 (TLR4) agonists are known to regress solid tumors, we observed that lipopolysaccharide (LPS) induces TOPORS via a TLR4‐TIR domain‐containing adapter‐inducing interferon‐β‐dependent pathway, which in turn modulates the transcription of tumor suppressor scaffold/matrix attachment region‐binding protein 1 (SMAR1, also known as BANP). ChIP analysis showed that TOPORS binds on the SMAR1 promoter and its occupancy increases upon LPS treatment. A previous study from our laboratory revealed that SMAR1 acts as a repressor of signal transducer and activator of transcription 3 (STAT3) transcription. Tumor growth, as well as tumor‐associated macrophage polarization, depends on the status of the STAT1:STAT3 ratio. LPS‐induced SMAR1 expression decreases STAT3 expression and also skews the macrophage polarization toward M1 phenotype. In contrast, LPS failed to polarize tumor‐associated macrophages to M1 phenotype in a SMAR1‐silenced condition, which shows the involvement of SMAR1 in dictating the fate of colorectal cancer progression. Identification of the molecular mechanism behind LPS‐mediated tumor regression would be crucial for designing cancer treatment strategies involving bacterial components.

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SMAR1 repression by pluripotency factors and consequent chemoresistance in breast cancer stem-like cells is reversed by aspirin

Cited by 22 publications

References 72 publications

Cellular Metabolomics Profiles Associated With Drug Chemosensitivity in AML

Cellular Metabolomics Profiles Associated With Drug Chemosensitivity in AML

SMAR1 attenuates the stemness of osteosarcoma cells via through suppressing ABCG2 transcriptional activity

RING finger protein TOPORS modulates the expression of tumor suppressor SMAR1 in colorectal cancer via the TLR4‐TRIF pathway

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