Histone deacetylase inhibitors differentially regulate c‑Myc expression in retinoblastoma cells

Yu, Na; Chen, Pei; Wang, Qiyun; Liang, Meixin; Qiu, Jin; Zhou, Pan; Yang, Meng; Yang, Panyang; Wu, Yihui; Han, Xiaokun; Ge, Jian; Zhuang, Jing; Yu, Keming

doi:10.3892/ol.2019.11111

Cited by 8 publications

(14 citation statements)

References 41 publications

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“…6 MYC has been reported to be overexpressed in 50-60% of all ESCC patients, and suppression of MYC was shown to reverse tumorigenesis in retinoblastoma, breast cancer, hepatocellular, pancreatic cancer and cervical cancer. [26][27][28][29][30][31][32][33] However, targeting MYC per se has proven to be very challenging because of its intrinsically disordered nature. Therefore, many researchers have looked at inhibiting MYC indirectly by blocking MYC transcription, blocking mRNA translation or targeting regulators of MYC protein stability.…”

Section: Discussionmentioning

confidence: 99%

<p>HSP90 Inhibitor Ganetespib (STA-9090) Inhibits Tumor Growth in c-Myc-Dependent Esophageal Squamous Cell Carcinoma</p>

Guan¹,

Zou²,

Liu³

et al. 2020

OTT

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Purpose: Currently, the paucity of classical effective pharmacological drugs to treat esophageal squamous cell carcinoma (ESCC) is a major problem. The c-Myc (MYC) protein is a promising target as it is overexpressed in ESCC. MYC is a sensitive client protein of the heat shock protein 90 (HSP90) and, therefore, targeting the HSP90-MYC axis by inhibition of HSP90 is a potential therapeutic strategy for ESCC. Here, we evaluated the clinical application value of the HSP90 inhibitor (Ganetespib, STA-9090) as an anti-cancer agent for MYC-positive ESCC. Materials and Methods: We first analyzed ESCC tissue microarrays and clinical tissue samples to determine MYC expression. The relationship between MYC and HSP90 was analyzed by co-immunoprecipitation assays and immunofluorescence. In in vitro cell models, cell growth was analyzed using the CCK-8 kit, and MYC protein expression was analyzed by Western blot. The in vivo antitumor activity of STA-9090 was assessed in two xenograft animal models. Results: We demonstrated that MYC-overexpressing ESCC cells were highly sensitive to STA-9090 treatment through suppressing ESCC cell proliferation, cell cycle progression and survival. Moreover, STA-9090 treatment decreased MYC expression, reducing the half-life of the MYC protein. We further established two xenograft mouse models using ESCC cells and clinical ESCC samples to validate the effectiveness of STA-9090 in vivo. In both xenograft models, STA-9090 substantially inhibited the growth of MYC-positive ESCC tumors in vivo. In contrast, STA-9090 treatment demonstrated no beneficial effects in mice with low-MYC expressing ESCC tumors. Conclusion: In conclusion, our data support that the HSP90 inhibitor, STA-9090, suppresses the expression of the MYC protein and interferes with HSP90-MYC protein-protein interaction. This, in turn, leads to inhibition of ESCC cell proliferation and promotion of apoptosis in ESCC cells in vitro and reduction of ESCC tumors in vivo. We propose, based on our findings, that STA-9090 is a potential novel therapeutic target for MYC-positive ESCC.

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Section: Discussionmentioning

confidence: 99%

<p>HSP90 Inhibitor Ganetespib (STA-9090) Inhibits Tumor Growth in c-Myc-Dependent Esophageal Squamous Cell Carcinoma</p>

Guan¹,

Zou²,

Liu³

et al. 2020

OTT

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“…This enhances the sensitivity to standard chemotherapeutic drugs such as etoposide. A recent study by Yu et al [29] have demonstrated that HDAC inhibitors trichostatin A, suberoylanilide hydroxamic acid, and MS-275 were also able to transcriptionally induce the expression of c-Myc in WERI-Rb1 cells which could provide new insights into the c-Myc expression mechanism and its bioactivity in RB cells. Another newly discovered class of HDACi, AR-42, has demonstrated antitumor effects by inducing apoptosis and cell cycle arrest in Y79 cells.…”

Section: Histone Deacetylase Inhibitors: Trichostatin a Suberoylanili...mentioning

confidence: 99%

Emerging New Therapeutics for Retinoblastoma

2022

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Background: Over the last few decades, chemotherapy has become the main treatment of retinoblastoma, delivered through various routes: intravenous (IVC), intra-arterial (IAC), and intravitreal (IvitC). Despite its efficacy, chemotherapy related toxicity (ocular and systemic) and recurrences due to resistant tumor clones are common, highlighting the need for novel therapeutic agents. Summary: Recent advances in our understanding of the molecular drivers of Rb1 tumorigenesis and mechanisms of tumor resistance have afforded opportunities to explore novel targets such as the MDMX–p53 pathway (Nutlin-3), Histone deacetylase inhibitors (HDACi), Spleen tyrosine kinase (SYK) inhibitors, and genetic and immune modulatory drugs. In this review we discuss the limitations of current therapeutic strategies, candidate cellular pathways, current evidence for newer targeted drugs, and offer a look towards the future. Key messages: Advances in the understanding of the molecular drivers of RB pathway have provided opportunities to explore novel drugs with targeted effects, improved bioavailability, and reduced chemotoxicity.

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“…Myc is an aberrantly expressed transcription factor that acts as a crucial player in many biological processes such as proliferation and differentiation of cells, and participates in the pathogenesis of several cancers [ 13 ]. For instance, the abnormal expression of Myc was implicated in the progression of retinoblastoma and proposed as a promising therapeutic target for the treatment of this malignancy [ 14 , 15 ] Moreover, a precious study demonstrated that CENPA hotspots could accumulate at the 8q24/Myc region and thus impact chromosome fragility of cancer cells [ 16 ]. B cell lymphoma-2 (Bcl2), an anti-apoptotic protein, was reported to facilitate cell proliferation and restrain apoptosis of retinoblastoma cells [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Knockdown of NRMT enhances sensitivity of retinoblastoma cells to cisplatin through upregulation of the CENPA/Myc/Bcl2 axis

Zhang

Liu

et al. 2022

Cell Death Discov.

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Chemotherapy resistance of tumor cells causes failure in anti-tumor therapies. Recently, N-terminal regulator of chromatin condensation 1 methyltransferase (NRMT) is abnormally expressed in different cancers. Hence, we speculate that NRMT may pay a crucial role in the development of chemosensitivity in retinoblastoma. We characterized the upregulation of NRMT in the developed cisplatin (CDDP)-resistant retinoblastoma cell line relative to parental cells. Loss-of-function experiments demonstrated that NRMT silencing enhanced chemosensitivity of retinoblastoma cells to CDDP. Next, NRMT was identified to enrich histone-H3 lysine 4 trimethylation in the promoter of centromere protein A (CENPA) by chromatin immunoprecipitation assay. Rescue experiments suggested that CENPA reduced chemosensitivity by increasing the viability and proliferation and reducing apoptosis of CDDP-resistant retinoblastoma cells, which was reversed by NRMT. Subsequently, CENPA was witnessed to induce the transcription of Myc and to elevate the expression of B cell lymphoma-2. At last, in vivo experiments confirmed the promotive effect of NRMT knockdown on chemosensitivity of retinoblastoma cells to CDDP in tumor-bearing mice. Taken together, NRMT is an inhibitor of chemosensitivity in retinoblastoma. Those findings shed new light on NRMT-targeted therapies for retinoblastoma.

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Histone deacetylase inhibitors differentially regulate c‑Myc expression in retinoblastoma cells

Cited by 8 publications

References 41 publications

<p>HSP90 Inhibitor Ganetespib (STA-9090) Inhibits Tumor Growth in c-Myc-Dependent Esophageal Squamous Cell Carcinoma</p>

<p>HSP90 Inhibitor Ganetespib (STA-9090) Inhibits Tumor Growth in c-Myc-Dependent Esophageal Squamous Cell Carcinoma</p>

Emerging New Therapeutics for Retinoblastoma

Knockdown of NRMT enhances sensitivity of retinoblastoma cells to cisplatin through upregulation of the CENPA/Myc/Bcl2 axis

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