KDM6A promotes imatinib resistance through YY1-mediated transcriptional upregulation of TRKA independently of its demethylase activity in chronic myelogenous leukemia

Zhang, Chengwan; Shen, Li; Zhu, Yifu; Xu, Ran; Deng, Zhong‐Liang; Liu, Xiaoning; Ding, Yihan; Shi, Yuye; Bei, Liye; Wei, Dongping; Thorne, Rick F.; Zhang, Xu Dong; Yu, Liang; Chen, Song

doi:10.7150/thno.50571

Cited by 24 publications

(21 citation statements)

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“…KDM6A may also possess oncogenic potential in CML and AML ( Figure 2 ), as high expression was observed in patients with poor prognosis [ 57 , 59 , 128 ]. In CML, KDM6A promotes imatinib-resistance through upregulation of TRKA, a high affinity receptor for the growth factor NGF [ 57 ]. Pro-survival TRKA/NGF signaling is associated with therapy resistance in hematological disorders [ 129 , 130 , 131 , 132 , 133 ].…”

Section: Resultsmentioning

confidence: 99%

“…Pro-survival TRKA/NGF signaling is associated with therapy resistance in hematological disorders [ 129 , 130 , 131 , 132 , 133 ]. Targeting KDM6A in CML cell lines and primary cells reduced TRKA levels and sensitized cells towards imatinib-induced apoptosis [ 57 ]. KDM6A is also required for cell expansion as its depletion significantly reduced proliferation in AML cell lines [ 58 ].…”

Section: Resultsmentioning

confidence: 99%

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The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

2021

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Histone methylation tightly regulates chromatin accessibility, transcription, proliferation, and cell differentiation, and its perturbation contributes to oncogenic reprogramming of cells. In particular, many myeloid malignancies show evidence of epigenetic dysregulation. Jumonji C (JmjC) domain-containing proteins comprise a large and diverse group of histone demethylases (KDMs), which remove methyl groups from lysines in histone tails and other proteins. Cumulating evidence suggests an emerging role for these demethylases in myeloid malignancies, rendering them attractive targets for drug interventions. In this review, we summarize the known functions of Jumonji C (JmjC) domain-containing proteins in myeloid malignancies. We highlight challenges in understanding the context-dependent mechanisms of these proteins and explore potential future pharmacological targeting.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

2021

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“…For example, Zhang et alreported that the histone lysine demethylase KDM6A was recruited to the NTRK1 promoter by the transcription factor YY1, then upregulation of the NTRK1-encoded protein TRKA activated downstream pathways to cause imatinib resistance. The authors identified the KDM6A/YY1/TRKA axis as a new imatinib resistance mechanism in CML [ 39 ]. Moreover, our previous studies reported that histone deacetylases (HDAC) and transcription factor retinoic X receptors (RXRs) cooperatively regulated HtrA1 (high temperature requirement factor serine peptidase 1) in cisplatin resistance, and targeting the HDAC/RXR/HtrA1 signaling pathway overcame the cisplatin resistance in NSCLC cells [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

An EHMT2/NFYA-ALDH2 signaling axis modulates the RAF pathway to regulate paclitaxel resistance in lung cancer

Wang

Liu

et al. 2022

Mol Cancer

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Background Lung cancer is a kind of malignancy with high morbidity and mortality worldwide. Paclitaxel (PTX) is the main treatment for non-small cell lung cancer (NSCLC), and resistance to PTX seriously affects the survival of patients. However, the underlying mechanism and potential reversing strategy need to be further explored. Methods We identified ALDH2 as a PTX resistance-related gene using gene microarray analysis. Subsequently, a series of functional analysis in cell lines, patient samples and xenograft models were performed to explore the functional role, clinical significance and the aberrant regulation mechanism of ALDH2 in PTX resistance of NSCLC. Furthermore, the pharmacological agents targeting ALDH2 and epigenetic enzyme were used to investigate the diverse reversing strategy against PTX resistance. Results Upregulation of ALDH2 expression is highly associated with resistance to PTX using in vitro and in vivo analyses of NSCLC cells along with clinicopathological analyses of NSCLC patients. ALDH2-overexpressing NSCLC cells exhibited significantly reduced PTX sensitivity and increased biological characteristics of malignancy in vitro and tumor growth and metastasis in vivo. EHMT2 (euchromatic histone lysine methyltransferase 2) inhibition and NFYA (nuclear transcription factor Y subunit alpha) overexpression had a cooperative effect on the regulation of ALDH2. Mechanistically, ALDH2 overexpression activated the RAS/RAF oncogenic pathway. NSCLC/PTX cells re-acquired sensitivity to PTX in vivo and in vitro when ALDH2 was inhibited by pharmacological agents, including the ALDH2 inhibitors Daidzin (DZN)/Disulfiram (DSF) and JIB04, which reverses the effect of EHMT2. Conclusion Our findings suggest that ALDH2 status can help predict patient response to PTX therapy and ALDH2 inhibition may be a promising strategy to overcome PTX resistance in the clinic.

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“…YY1 is shown to regulate lots of downstream molecules including tumor suppressors and oncogenes therefore involves in various homeostatic processes and diseases including cancer [19,20]. YY1 works as a transcription factor and is associated with cell differentiation [21], apoptosis [22] and tumorigenesis [23].It is reported that the expression level or function of YY1 has two sides in different cancers [24] ; most researches indicate YY1 is highly expressed in a range of cancer typesincluding breast [25,26], gastric, brain, liver, lung and melanoma [27].However, YY1 is also reported to play a tumor suppressor role particularly in the case of pancreatic cancer [28].…”

Section: Introductionmentioning

confidence: 99%

JAC1 Targets YY1-Mediated JWA/p38 MAPK Signaling to Inhibit Proliferation and Induce Apoptosis in TNBC

Zhai

Ren

Shu

et al. 2022

Preprint

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Background:Triple negative breast cancer (TNBC)is a type of breast cancer with poor prognosis, and still has no adequate therapeutic target and ideal medicine.The public database and the relative studies have shown that low expression of JWA is closely related to the poor overall survival in many cancers including breast cancer. However, the precise biological functions and behind mechanisms of JWA in TNBC are still unclear.Methods:Both TCGA and GEO databases were used to confirm the relationship between expression levels of JWA and overall survival inTNBC cases.JAC1, an agonisticsmall compound of JWA gene, was used in TNBC modelsin vitro and in vivo. The routine cellular and molecular assays include CCK-8, colony formation, EdUincorporation, the flow cytometry, Western blot, immunohistochemistry,immune-fluorescence microscopy and reporter gene assays were conducted in this study.Results:Low expression of JWA was associated with poor prognosis in TNBC patients. JAC1 treatment inhibited TNBCcells proliferation and promoted apoptosis in vitro and in vivo. JAC1 specifically combined and targeted YY1toeliminate its transcriptional inhibition on JWA gene.At the same time, JAC1promoted ubiquitination and degradation of YY1. The rescued JWA induced G1 phase arrest and apoptosis in TNBC cellsthrough the p38 MAPK signaling pathway. In addition, JAC1 disrupted the interaction between YY1 and HSF1, and suppressed the oncogenic role of HSF1 in TNBC throughp-Aktsignaling pathway.Conclusions:We discovered for the first time that JAC1 is a YY1 targeting compoundand maybe a potential therapeutic agent for TNBC.

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KDM6A promotes imatinib resistance through YY1-mediated transcriptional upregulation of TRKA independently of its demethylase activity in chronic myelogenous leukemia

Cited by 24 publications

References 53 publications

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

An EHMT2/NFYA-ALDH2 signaling axis modulates the RAF pathway to regulate paclitaxel resistance in lung cancer

JAC1 Targets YY1-Mediated JWA/p38 MAPK Signaling to Inhibit Proliferation and Induce Apoptosis in TNBC

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