Contribution of STAT3 and RAD23B in Primary Sézary Cells to Histone Deacetylase Inhibitor FK228 Resistance

Butler, Rosie M.; McKenzie, Robert C.; Jones, Christine L.; Flanagan, Charlotte E.; Woollard, Wesley J.; Demontis, Maria Piera; Ferreira, Sandra Reis; Tosi, Isabella; John, Susan; Whittaker, Sean; Mitchell, Tracey

doi:10.1016/j.jid.2019.03.1130

Cited by 10 publications

(5 citation statements)

References 52 publications

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“…More importantly, we further revealed that the downregulation of CFHR3 increased HCC cell growth and metastasis, which was suppressed by the STAT3 inhibitor, S3I-201. As known to us, phosphorylated STAT3 constitutes an essential pathway that regulates the signaling of miscellaneous biological activities including drug resistance, cell metastasis as well as cell proliferation [ 34 , 35 ]. In our study, we confirm that the phosphorylated STAT3 induced by CFHR3 downregulation suppressed p53 expression to promote HCC progression.…”

Section: Discussionmentioning

confidence: 99%

The miR-590-3p/CFHR3/STAT3 signaling pathway promotes cell proliferation and metastasis in hepatocellular carcinoma

Wan

Luo

et al. 2022

Aging

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Accumulating evidence has indicated that Complement factor H-related 3 (CFHR3) plays an essential role in various diseases. However, the biological functions of CFHR3 in hepatocellular carcinoma (HCC) remain largely unclear. Therefore, we perform a further study on CFHR3 in HCC. In this article, we report the suppressive role of CFHR3 in the proliferation and metastasis of HCC cells. CFHR3 downregulation is closely associated with large (T3-T4) HCC, tumor recurrence, and advanced (stage III-IV) clinical stage, functioning as an independent factor for the prognoses of HCC patients. Knockdown of CFHR3 promotes proliferation, migration, and invasion of HCC cells. Mechanistically, downregulation of CFHR3 is induced by miR-590-3p binding to the 3' untranslated region (UTR) of CFHR3. CFHR3 downregulation promotes the phosphorylation of STAT3 protein, thereby suppressing p53 expression. The promotional effect upon downregulation of CFHR3 induced by CFHR3 stable knockdown or miR-590-3p on HCC cell malignant phenotypes is attenuated by STAT3 inhibitor, S3I-201. In conclusion, our results reveal that CFHR3 is a protective biomarker for HCC patients, and targeting the miR-590-3p/CFHR3/p-STAT3/p53 signaling axis provides a promising strategy for HCC therapeutics.

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Section: Discussionmentioning

confidence: 99%

The miR-590-3p/CFHR3/STAT3 signaling pathway promotes cell proliferation and metastasis in hepatocellular carcinoma

Wan

Luo

et al. 2022

Aging

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“… 83 Several other lines of evidence support that STAT3 plays a role in HDACi resistance: (1) STAT3 phosphorylation was associated with vorinostat resistance, 84 (2) JAK inhibition boosted the efficacy of romidepsin, 85 and (3) Sézary cells carrying the constitutively active variant of STAT3 (Y640F) were less sensitive to romidepsin-induced apoptosis. 86 Importantly, eradication of SE-producing S aureus by antibiotics inhibited STAT3 activation in vivo in patients with CTCL. 35 Taken together, these findings support the hypothesis that SE-producing S aureus can induce STAT3-dependent resistance to drugs such as HDACi.…”

Section: Discussionmentioning

confidence: 99%

Staphylococcus aureusinduces drug resistance in cancer T cells in Sézary syndrome

Vadivel,

Willerslev-Olsen,

Namini

et al. 2024

Blood

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Patients with Sézary syndrome (SS), a leukemic variant of cutaneous T cell lymphoma (CTCL), are prone to Staphylococcus aureus (S. aureus) infections and have a poor prognosis due to treatment-resistance. Here, we report that S. aureus and staphylococcal enterotoxins (SE) induce drug resistance in malignant T-cells against therapeutics commonly used in CTCL. Supernatant from patient-derived, SE-producing S. aureus and recombinant SE significantly inhibit cell death induced by HDAC inhibitor romidepsin in primary malignant T-cells from SS patients. Bacterial killing by engineered, bacteriophage-derived, S. aureus-specific endolysin (XZ.700) abrogates the effect of S. aureus supernatant. Likewise, mutations in MHC Class II binding sites of SE type-A (SEA) and anti-SEA antibody block induction of resistance. Importantly, SE also triggers resistance to other HDAC inhibitors (vorinostat and resminostat) and chemotherapeutic drugs (doxorubicin and etoposide). Multimodal single-cell sequencing indicates TCR, NFB, and JAK/STAT signaling pathways (previously associated with drug-resistance) as putative mediators of SE-induced drug resistance. In support, inhibition of TCR-signaling and Protein Kinase C (upstream of NFB) counteracts SE-induced rescue from drug-induced cell death. Inversely, SE cannot rescue from cell death induced by proteasome/NFB inhibitor bortezomib. Inhibition of JAK/STAT only blocks SE-induced rescue of malignant T-cells in some but not all patients, suggesting two distinct ways SE can induce drug resistance. In conclusion, we show that S. aureus enterotoxins induce drug-resistance in primary malignant T-cells. These findings suggest that S. aureus enterotoxins cause clinical treatment-resistance in SS patients and that anti-bacterial measures may improve the outcome of cancer-directed therapy in patients harboring S. aureus.

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“…Cytogenetic and genomic studies have recently provided data on the molecular mechanism for apoptosis resistance in CTCL malignant T cells and data on the molecular heterogeneity of CTCL cell populations ( Figure 2 ) ( 58 ). In one study, STAT3 and RAD23B genotypes were reported to influence primary HDACi sensitivity in Sézary cells ( 64 ). In another study, persistent activation of STAT1 and pSTAT3 was shown to correlate with resistance to vorinostat in patients with CTCL ( 65 ).…”

Section: Histone Modification In Ctclmentioning

confidence: 99%

Epigenetics in the Pathogenesis and Treatment of Cutaneous T-Cell Lymphoma

Zhang

2021

Front. Oncol.

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Cutaneous T-cell lymphomas (CTCLs) comprise a group of heterogeneous diseases involving malignant T cells. The pathogenesis and etiology of CTCL are still unclear, although a large number of genetic and epidemiological studies on CTCL have been conducted. Most CTCLs have an indolent course, making early diagnosis difficult. Once large-cell transformation occurs, CTCL progresses to more aggressive types, resulting in an overall survival of less than five years. Epigenetic drugs, which have shown certain curative effects, have been selected as third-line drugs in patients with relapsing and refractory CTCL. Many studies have also identified epigenetic biomarkers from tissues and peripheral blood of patients with CTCL and suggested that epigenetic changes play a role in malignant transformation and histone deacetylase inhibitor (HDACi) resistance in CTCL. Single-cell sequencing has been applied in CTCL studies, revealing heterogeneity in CTCL malignant T cells. The mechanisms of HDACi resistance have also been described, further facilitating the discovery of novel HDACi targets. Despite the heterogeneity of CTCL disease and its obscure pathogenesis, more epigenetic abnormalities have been gradually discovered recently, which not only enables us to understand CTCL disease further but also improves our understanding of the specific role of epigenetics in the pathogenesis and treatment. In this review, we discuss the recent discoveries concerning the pathological roles of epigenetics and epigenetic therapy in CTCL.

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Contribution of STAT3 and RAD23B in Primary Sézary Cells to Histone Deacetylase Inhibitor FK228 Resistance

Cited by 10 publications

References 52 publications

The miR-590-3p/CFHR3/STAT3 signaling pathway promotes cell proliferation and metastasis in hepatocellular carcinoma

The miR-590-3p/CFHR3/STAT3 signaling pathway promotes cell proliferation and metastasis in hepatocellular carcinoma

Staphylococcus aureusinduces drug resistance in cancer T cells in Sézary syndrome

Epigenetics in the Pathogenesis and Treatment of Cutaneous T-Cell Lymphoma

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