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Targeting “undruggable” c-Myc protein by synthetic lethality

Chen Wang, Hui Fang, Jiawei Zhang, Ying Gu

《医学前沿（英文）》 2021年第15卷第4期页码 541-550 doi: 10.1007/s11684-020-0780-y

摘要： Synthetic lethal screening, which exploits the combination of mutations that result in cell death, is a promising method for identifying novel drug targets. This method provides a new avenue for targeting “undruggable” proteins, such as c-Myc. Here, we revisit current methods used to target c-Myc and discuss the important functional nodes related to c-Myc in non-oncogene addicted network, whose inhibition may cause a catastrophe for tumor cell destiny but not for normal cells. We further discuss strategies to identify these functional nodes in the context of synthetic lethality. We review the progress and shortcomings of this research field and look forward to opportunities offered by synthetic lethal screening to treat tumors potently.

关键词： synthetic lethality undruggable transcription factor c-Myc

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Chidamide inhibits the NOTCH1-MYC signaling axis in T-cell acute lymphoblastic leukemia

《医学前沿（英文）》 2022年第16卷第3期页码 442-458 doi: 10.1007/s11684-021-0877-y

摘要： T-cell acute lymphoblastic leukemia (T-ALL) is one of the most dangerous hematological malignancies, with high tumor heterogeneity and poor prognosis. More than 60% of T-ALL patients carry NOTCH1 gene mutations, leading to abnormal expression of downstream target genes and aberrant activation of various signaling pathways. We found that chidamide, an HDAC inhibitor, exerts an antitumor effect on T-ALL cell lines and primary cells including an anti-NOTCH1 activity. In particular, chidamide inhibits the NOTCH1-MYC signaling axis by down-regulating the level of the intracellular form of NOTCH1 (NICD1) as well as MYC, partly through their ubiquitination and degradation by the proteasome pathway. We also report here the preliminary results of our clinical trial supporting that a treatment by chidamide reduces minimal residual disease (MRD) in patients and is well tolerated. Our results highlight the effectiveness and safety of chidamide in the treatment of T-ALL patients, including those with NOTCH1 mutations and open the way to a new therapeutic strategy for these patients.

关键词： T-cell acute lymphoblastic leukemia HDAC inhibitor chidamide NOTCH1 MYC ubiquitination

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The MYC transcription factor network: balancing metabolism, proliferation and oncogenesis

null

《医学前沿（英文）》 2018年第12卷第4期页码 412-425 doi: 10.1007/s11684-018-0650-z

摘要：

Transcription factor networks have evolved in order to control, coordinate, and separate, the functions of distinct network modules spatially and temporally. In this review we focus on the MYC network (also known as the MAX-MLX Network), a highly conserved super-family of related basic-helix-loop-helix-zipper (bHLHZ) proteins that functions to integrate extracellular and intracellular signals and modulate global gene expression. Importantly the MYC network has been shown to be deeply involved in a broad spectrum of human and other animal cancers. Here we summarize molecular and biological properties of the network modules with emphasis on functional interactions among network members. We suggest that these network interactions serve to modulate growth and metabolism at the transcriptional level in order to balance nutrient demand with supply, to maintain growth homeostasis, and to influence cell fate. Moreover, oncogenic activation of MYC and/or loss of a MYC antagonist, results in an imbalance in the activity of the network as a whole, leading to tumor initiation, progression and maintenance.

关键词： network transcription cancer MYC MAX MLX

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Abnormal expression of c-Myc in human bronchial epithelial cells malignantly transformed by anti-BPDE

FU Juan, JIANG Yiguo, CHEN Xuemin

《医学前沿（英文）》 2008年第2卷第4期页码 380-385 doi: 10.1007/s11684-008-0073-3

摘要： Anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (anti-BPDE) is a metabolite of benzo[a]pyrene (B[a]P) and acts as a potent mutagen in mammalian systems. However, molecular mechanisms related to anti-BPDE-induced carcinogenesis are poorly understood. Here, we investigated the expression of proto-oncogene c- in human bronchial epithelial cells (16HBE-T) transformed by exposure to anti-BPDE. The levels of mRNA and protein of c-Myc were examined in the 16HBE-T and vehicle-treated control cells (16HBE-N) by using different methods respectively, including reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative real-time PCR (Q-PCR), western blot and immunocytochemical methods. The level of c- mRNA appeared to be significantly increased in 16HBE-T, as compared with those of the 16HBE-N. Likewise, the expression of c-Myc protein was significantly enhanced as compared with those of the control cells. Moreover, the localization of c-Myc protein shows mainly nuclear staining in 16HBE-T. In conclusion, the abnormal expression of c-Myc was present in anti-BPDE malignantly transformed 16HBE cells, which may be involved in the carcinogenesis molecular mechanism of anti-BPDE.

关键词： transcriptase-polymerase vehicle-treated understood molecular mechanism different