ZNF516 suppresses EGFR by targeting the CtBP/LSD1/CoREST complex to chromatin

Li, Lifang; Liu, Xinhua; He, Lin; Yang, Jianguo; Pei, Fei; Li, Wanjin; Liu, Shumeng; Chen, Zhe; Xie, Guojia; Xu, Bing; Xia, Ting; Zhang, Zihan; Jin, Tong; Liu, Xujun; Zhang, Wenting; Yuan, Shuai; Yang, Ziran; Wu, Chongyang; Zhang, Yu; Yang, Xiaohan; Yi, Xin; Liang, Jing; Shang, Yongfeng; Sun, Luyang

doi:10.1038/s41467-017-00702-5

Cited by 46 publications

(37 citation statements)

References 61 publications

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“…Interaction of CtBP2 with Other Transcriptional Coregulators Is Facilitated by W324. CtBP associates with CoREST among other chromatin modifier proteins to transcriptionally coregulate (repress and activate) numerous cancer-related tumor suppressors and oncogenes, including CDH1 and EGFR (Quinlan et al, 2006;Li et al, 2017). Having established that W324 influences CtBP2's oligomerization capabilities, we further inquired whether physiologic functions, such as CtBP coassociation with CoREST (Choi et al, 2013), depend on intact W324.…”

Section: Resultsmentioning

confidence: 99%

“…C-terminal binding proteins (CtBP)1/2 play central roles as transcriptional coregulators in metazoan development and human diseases alike (Chinnadurai, 2000). Although a precise mechanism of coregulation is yet to be described, a plausible mechanism involves CtBP oligomerization in the presence of NAD(H), where one or more CtBP monomers interact with DNA-interacting proteins (e.g., ZNF516) (Li et al, 2017). Following oligomerization, chromatin modifiers can be recruited to the CtBP oligomer to form a promoter-bound supercomplex that actively regulates transcription (Shi et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Active-Site Tryptophan, the Target of Antineoplastic C-Terminal Binding Protein Inhibitors, Mediates Inhibitor Disruption of CtBP Oligomerization and Transcription Coregulatory Activities

Dcona¹,

Damle²,

Zárate‐Pérez³

et al. 2019

Mol Pharmacol

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C-terminal binding proteins (CtBP1/2) are oncogenic transcriptional coregulators and dehydrogenases often overexpressed in multiple solid tumors, including breast, colon, and ovarian cancer, and associated with poor survival. CtBPs act by repressing expression of genes responsible for apoptosis (e.g., PUMA, BIK) and metastasis-associated epithelial-mesenchymal transition (e.g., CDH1), and by activating expression of genes that promote migratory and invasive properties of cancer cells (e.g., TIAM1) and genes responsible for enhanced drug resistance (e.g., MDR1). CtBP's transcriptional functions are also critically dependent on oligomerization and nucleation of transcriptional complexes. Recently, we have developed a family of CtBP dehydrogenase inhibitors, based on the parent 2-hydroxyimino-3-phenylpropanoic acid (HIPP), that specifically disrupt cancer cell viability, abrogate CtBP's transcriptional function, and block polyp formation in a mouse model of intestinal polyposis that depends on CtBP's oncogenic functions. Crystallographic analysis revealed that HIPP interacts with CtBP1/2 at a conserved active site tryptophan (W318/324; CtBP1/2) that is unique among eukaryotic D2-dehydrogenases. To better understand the mechanism of action of HIPP-class inhibitors, we investigated the contribution of W324 to CtBP2's biochemical and physiologic activities utilizing mutational analysis. Indeed, W324 was necessary for CtBP2 self-association, as shown by analytical ultracentrifugation and in vivo cross-linking. Additionally, W324 supported CtBP's association with the transcriptional corepressor CoREST, and was critical for CtBP2 induction of cell motility. Notably, the HIPP derivative 4-chloro-HIPP biochemically and biologically phenocopied mutational inactivation of CtBP2 W324. Our data support further optimization of W318/W324-interacting CtBP dehydrogenase inhibitors that are emerging as a novel class of cancer cell-specific therapeutic.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Active-Site Tryptophan, the Target of Antineoplastic C-Terminal Binding Protein Inhibitors, Mediates Inhibitor Disruption of CtBP Oligomerization and Transcription Coregulatory Activities

Dcona¹,

Damle²,

Zárate‐Pérez³

et al. 2019

Mol Pharmacol

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“…The ChIP assay was performed as described previously (Li et al, ; Yao et al, ). Briefly, VSMCs were treated with 40 ng·ml −1 PDGF‐BB for 36 hr.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of polycomb repressor complex 2 ameliorates neointimal hyperplasia by suppressing trimethylation of H3K27 in vascular smooth muscle cells

Liang

Cai

et al. 2019

British J Pharmacology

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Background and Purpose The increased proliferation and migration of vascular smooth muscle cells (VSMCs) after arterial injury contributes greatly to the pathogenesis of neointimal hyperplasia. As a major component of epigenetics, histone methylation plays an important role in several cardiovascular diseases. However, its role in restenosis is still unclear. Experimental Approach Human aortic VSMCs were challenged with PDGF‐BB, and total histones were extracted and analysed by HPLC/MS. For the in vivo study, rats were subjected to wire‐guided common carotid injury. Key Results PDGF‐BB markedly increased the H3K27me3 level, as demonstrated by use of HPLC/MS and confirmed by western blot analysis. Enhancer of zeste homologue 2 (EZH2), the histone H3K27 methyltransferase component of polycomb repressive complex 2, was also up‐regulated by PDGF‐BB in VSMCs, and in the neointimal hyperplasia induced by wire injury of the rat carotid artery. Furthermore, inhibiting H3K27me3 by treatment with 3‐μM UNC1999, an EZH2/1 inhibitor, significantly suppressed PDGF‐BB‐induced VSMC proliferation compared with the PDGF‐BB‐treated group. Consistently, neointimal formation was significantly attenuated by oral or perivascular administration of UNC1999 compared with the sham group. Mechanistically, the increase in H3K27me3 inhibited the transcription of the cyclin‐dependent kinase inhibitor p16INK4A and thus promoted VSMC proliferation. Conclusions and Implications Vascular injury elevated the expression of EZH2 and the downstream target H3K27me3, which suppressed p16INK4A expression in VSMCs and promoted VSMC proliferation and neointimal hyperplasia. EZH2 inhibition might be a potential therapeutic target for restenosis.

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“…3F). CTBP2 is a transcriptional corepressor (Furusawa et al 1999) and is a component of the CtBP/LSD1/CoREST repressor complex (Li et al 2017). Ring finger protein BMI1 is a core component of the polycomb-repressive complex 1 (PRC1) (Gray et al 2016), which plays a role in epigenetic regulation of gene silencing.…”

Section: Bcl6 Is Essential For Positive Regulation Of Mll In Pre-b Cellsmentioning

confidence: 99%

Rationale for targeting BCL6 inMLL-rearranged acute lymphoblastic leukemia

et al. 2019

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Chromosomal rearrangements of the mixed lineage leukemia (MLL) gene occur in ∼10% of B-cell acute lymphoblastic leukemia (B-ALL) and define a group of patients with dismal outcomes. Immunohistochemical staining of bone marrow biopsies from most of these patients revealed aberrant expression of BCL6, a transcription factor that promotes oncogenic B-cell transformation and drug resistance in B-ALL. Our genetic and ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) analyses showed that MLL-AF4 and MLL-ENL fusions directly bound to the BCL6 promoter and up-regulated BCL6 expression. While oncogenic MLL fusions strongly induced aberrant BCL6 expression in B-ALL cells, germline MLL was required to up-regulate Bcl6 in response to physiological stimuli during normal B-cell development. Inducible expression of Bcl6 increased MLL mRNA levels, which was reversed by genetic deletion and pharmacological inhibition of Bcl6, suggesting a positive feedback loop between MLL and BCL6. Highlighting the central role of BCL6 in MLL-rearranged B-ALL, conditional deletion and pharmacological inhibition of BCL6 compromised leukemogenesis in transplant recipient mice and restored sensitivity to vincristine chemotherapy in MLL-rearranged B-ALL patient samples. Oncogenic MLL fusions strongly induced transcriptional activation of the proapoptotic BH3-only molecule BIM, while BCL6 was required to curb MLL-induced expression of BIM. Notably, peptide (RI-BPI) and small molecule (FX1) BCL6 inhibitors derepressed BIM and synergized with the BH3-mimetic ABT-199 in eradicating MLL-rearranged B-ALL cells. These findings uncover MLL-dependent transcriptional activation of BCL6 as a previously unrecognized requirement of malignant transformation by oncogenic MLL fusions and identified BCL6 as a novel target for the treatment of MLLrearranged B-ALL.

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ZNF516 suppresses EGFR by targeting the CtBP/LSD1/CoREST complex to chromatin

Cited by 46 publications

References 61 publications

Active-Site Tryptophan, the Target of Antineoplastic C-Terminal Binding Protein Inhibitors, Mediates Inhibitor Disruption of CtBP Oligomerization and Transcription Coregulatory Activities

Active-Site Tryptophan, the Target of Antineoplastic C-Terminal Binding Protein Inhibitors, Mediates Inhibitor Disruption of CtBP Oligomerization and Transcription Coregulatory Activities

Inhibition of polycomb repressor complex 2 ameliorates neointimal hyperplasia by suppressing trimethylation of H3K27 in vascular smooth muscle cells

Rationale for targeting BCL6 inMLL-rearranged acute lymphoblastic leukemia

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