Targeting Myc Interacting Proteins as a Winding Path in Cancer Therapy

Zhou, Yihui; Gao, Xiaomeng; Meng, Yuan; Yang, Bo; He, Qiaojun; Cao, Ji

doi:10.3389/fphar.2021.748852

Cited by 14 publications

(11 citation statements)

References 161 publications

(182 reference statements)

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“…In tumors, the low expression and short half-life of Myc can be reversed, which can lead to tumorigenesis. Proteins that directly interact with different Myc domains can affect the transcription of Myc target genes and regulate the stability of Myc through post-translational modifications, such as acetylation, methylation, and phosphorylation ( Zhou et al, 2021 ). In acute myeloid leukemia, Myc directly inhibits the expression of TFEB (a transcription factor regulated by mTORC1) and regulates DNA methylation and cell differentiation ( Wu and Eisenman, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Exploration of the effect of Celastrol on protein targets in nasopharyngeal carcinoma: Network pharmacology, molecular docking and experimental evaluations

et al. 2022

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Background: Celastrol, an important extract of Tripterygium wilfordii, shows strong antitumor activity in a variety of tumors including nasopharyngeal carcinoma (NPC). However, little is known about its targets in NPC. We aimed to screen the key gene targets of Celastrol in the treatment of NPC by means of in silico analyses (including network pharmacology and molecular docking) and experimental evaluations.Methods: The main target genes of Celastrol and the genes related to NPC were obtained by retrieving the relevant biological databases, and the common targets were screened. Protein-protein interaction analysis was used to screen the hub genes. Then, a “compound-target-disease” network model was created and molecular docking was used to predict the binding of Celastrol to the candidate hub proteins. Afterward, the expression changes of the candidate genes under the administration of Celastrol were verified in vitro and in vivo.Results: Sixty genes common to Celastrol and NPC were screened out, which may be related to numerous biological processes such as cell proliferation, apoptosis, and tube development, and enriched in various pathways such as PI3K- Akt, EGFR tyrosine kinase inhibitor resistance, and Apoptosis. The tight binding ability of the candidate hub proteins (TNF, VEGFA, and IL6) to Celastrol was predicted by molecular docking [Docking energy: TNF, −6.08; VEGFA,−6.76; IL6,−6.91(kcal/mol)]. In vitro experiments showed that the expression of TNF and VEGFA decreased while the expression of IL6 increased in NPC cells (CNE2 and HONE1) treated with Celastrol. In vivo experiments suggested that Celastrol significantly reduced the weight and volume of the transplanted tumors in tumor-bearing mice in vivo. The expression of TNF, VEGFA, and IL6 in the transplanted tumor cells could be regulated by using Celastrol, and the expression trends were consistent with the in vitro model.Conclusion: Several gene targets have been filtered out as the core targets of Celastrol in the treatment of NPC, which might be involved in a variety of signaling pathways. Hence, Celastrol may exert its anti-NPC activity through multiple targets and multiple pathways, which will provide new clues for further research. Future experiments are warranted to validate the findings.

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Section: Discussionmentioning

confidence: 99%

Exploration of the effect of Celastrol on protein targets in nasopharyngeal carcinoma: Network pharmacology, molecular docking and experimental evaluations

et al. 2022

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“…The central domain consists of a proline-rich PEST segment, a calpain cleavage site (CAPN) responsible for cytosolic MYC partial cleavage of the C-terminus producing “MYC-nick”, and a nuclear localization sequence (NLS). Six highly conserved regions dubbed MYC homology boxes (MBs 0–IV) are sequentially distributed across TAD and the central domain, which bind to different MYC interactors and thus enable MYC to regulate distinct enzymatic reactions throughout the transcriptional process (Figure B) …”

Section: Biochemistry Of Mycmentioning

confidence: 99%

“…Six highly conserved regions dubbed MYC homology boxes (MBs 0−IV) are sequentially distributed across TAD and the central domain, which bind to different MYC interactors and thus enable MYC to regulate distinct enzymatic reactions throughout the transcriptional process (Figure 1B). 21 Proteomic profiling of the MB interactomes has revealed that half of the MYC interactors require one or more MBs for binding wherein two MBs, MB0 and MBII, are universally required for transformation. 22 It should be appreciated that the interactome MB0 accelerates the transcription process by binding to the general transcription factor IIF (TFIIF) and also recruits PP1 phosphatase via cofactors to regulate MYC activity and stability.…”

Section: ■ Introductionmentioning

confidence: 99%

Demystifying the Druggability of the MYC Family of Oncogenes

et al. 2023

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The MYC family of oncogenes (MYC, MYCN, and MYCL) encodes a basic helix−loop−helix leucine zipper (bHLHLZ) transcriptional regulator that is responsible for moving the cell through the restriction point. Through the HLHZIP domain, MYC heterodimerizes with the bHLHLZ protein MAX, which enables this MYC-MAX complex to bind to E-box regulatory DNA elements thereby controlling transcription of a large group of genes and their proteins. Translationally, MYC is one of the foremost oncogenic targets, and deregulation of expression of the MYC family gene/proteins occurs in over half of all human tumors and is recognized as a hallmark of cancer initiation and maintenance. Additionally, unexpected roles for this oncoprotein have been found in cancers that nominally have a non-MYC etiology. Although MYC is rarely mutated, its gain of function in cancer results from overexpression or from amplification. Moreover, MYC is a pleiotropic transcription factor possessing broad pathogenic prominence making it a coveted cancer target. A widely held notion within the biomedical research community is that the reliable modulation of MYC represents a tremendous therapeutic opportunity given its role in directly potentiating oncogenesis. However, the MYC-MAX heterodimer interaction contains a large surface area with a lack of well-defined binding sites creating the perception that targeting of MYC-MAX is forbidding. Here, we discuss the biochemistry behind MYC and MYC-MAX as it relates to cancer progression associated with these transcription factors. We also discuss the notion that MYC should no longer be regarded as undruggable, providing examples that a therapeutic window is achievable despite global MYC inhibition.

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“…c-MYC is documented to be one of the most up-regulated oncogenes in different types of cancers [ 25 , 26 ]. c-MYC alteration has been reported in 9.92% of breast carcinoma patients [ 27 ].…”

Section: C-myc In Er+ve Breast Cancermentioning

confidence: 99%

“…In this manner, c-MYC can repress MIZ1 target genes; some of which belong to cell cycle inhibitors such as CDKN1A (p21) and CDKN2B (INK4B) [23,24]. c-MYC is documented to be one of the most up-regulated oncogenes in different types of cancers [25,26]. c-MYC alteration has been reported in 9.92% of breast carcinoma patients [27].…”

Section: C-myc In Er+ve Breast Cancermentioning

confidence: 99%

Targeting Ribosome Biogenesis to Combat Tamoxifen Resistance in ER+ve Breast Cancer

Tsoi

You

Leung

et al. 2022

Cancers

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Breast cancer is a heterogeneous disease. Around 70% of breast cancers are estrogen receptor-positive (ER+ve), with tamoxifen being most commonly used as an adjuvant treatment to prevent recurrence and metastasis. However, half of the patients will eventually develop tamoxifen resistance. The overexpression of c-MYC can drive the development of ER+ve breast cancer and confer tamoxifen resistance through multiple pathways. One key mechanism is to enhance ribosome biogenesis, synthesising mature ribosomes. The over-production of ribosomes sustains the demand for proteins necessary to maintain a high cell proliferation rate and combat apoptosis induced by therapeutic agents. c-MYC overexpression can induce the expression of eIF4E that favours the translation of structured mRNA to produce oncogenic factors that promote cell proliferation and confer tamoxifen resistance. Either non-phosphorylated or phosphorylated eIF4E can mediate such an effect. Since ribosomes play an essential role in c-MYC-mediated cancer development, suppressing ribosome biogenesis may help reduce aggressiveness and reverse tamoxifen resistance in breast cancer. CX-5461, CX-3543 and haemanthamine have been shown to repress ribosome biogenesis. Using these chemicals might help reverse tamoxifen resistance in ER+ve breast cancer, provided that c-MYC-mediated ribosome biogenesis is the crucial factor for tamoxifen resistance. To employ these ribosome biogenesis inhibitors to combat tamoxifen resistance in the future, identification of predictive markers will be necessary.

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Targeting Myc Interacting Proteins as a Winding Path in Cancer Therapy

Cited by 14 publications

References 161 publications

Exploration of the effect of Celastrol on protein targets in nasopharyngeal carcinoma: Network pharmacology, molecular docking and experimental evaluations

Exploration of the effect of Celastrol on protein targets in nasopharyngeal carcinoma: Network pharmacology, molecular docking and experimental evaluations

Demystifying the Druggability of the MYC Family of Oncogenes

Targeting Ribosome Biogenesis to Combat Tamoxifen Resistance in ER+ve Breast Cancer

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