EGFR–c-Src-Mediated HDAC3 Phosphorylation Exacerbates Invasion of Breast Cancer Cells

Kwak, Sungmin; Seo, Jae-Sung; Sung, Gi‐Jun; Song, Jaeki; Jeong, Ja A; Lee, Seung‐Hyun; Yoon, Ho Geun; Choi, Hyo‐Kyoung; Choi, Kyung‐Chul

doi:10.3390/cells8080930

Cited by 20 publications

(11 citation statements)

References 50 publications

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“…In this study, we have demonstrated that the interaction between HIPK2 and HDAC3 was increased in LPS-treated macrophages, and HIPK2 phosphorylates HDAC3 at Ser374 to inactivate its deacetylase activity. So far, only four phosphorylation sites in HDAC3 have been identified to enhance its deacetylase activity, including Ser424 (phosphorylated by protein kinase CK2) (18), Tyr325, Tyr328, and Tyr331 (phosphorylated by proto-oncogene tyrosine-protein kinase Src) (46,47). In contrast, our study has identified phosphorylation of Ser374 as an inhibitory site to decreases the deacetylase activity of HDAC3.…”

Section: Discussioncontrasting

confidence: 53%

HIPK2 phosphorylates HDAC3 for NF-κB acetylation to ameliorate colitis-associated colorectal carcinoma and sepsis

Zhang

Feng

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Although inflammation is critical for the clearance of pathogens, uncontrolled inflammation also contributes to the development of multiple diseases such as cancer and sepsis. Since NF-κB–mediated transactivation in the nucleus is pivotal downstream of various stimuli to induce inflammation, searching the nuclear-localized targets specifically regulating NF-κB activation will provide important therapeutic application. Here, we have identified that homeodomain-interacting protein kinase 2 (HIPK2), a nuclear serine/threonine kinase, increases its expression in inflammatory macrophages. Importantly, HIPK2 deficiency or overexpression could enhance or inhibit inflammatory responses in LPS-stimulated macrophages, respectively. HIPK2-deficient mice were more susceptible to LPS-induced endotoxemia and CLP-induced sepsis. Adoptive transfer of Hipk2+/− bone marrow cells (BMs) also aggravated AOM/DSS-induced colorectal cancer. Mechanistically, HIPK2 bound and phosphorylated histone deacetylase 3 (HDAC3) at serine 374 to inhibit its enzymatic activity, thus reducing the deacetylation of p65 at lysine 218 to suppress NF-κB activation. Notably, the HDAC3 inhibitors protected wild-type or Hipk2−/− BMs-reconstituted mice from LPS-induced endotoxemia. Our findings suggest that the HIPK2-HDAC3-p65 module in macrophages restrains excessive inflammation, which may represent a new layer of therapeutic mechanism for colitis-associated colorectal cancer and sepsis.

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Section: Discussioncontrasting

confidence: 53%

HIPK2 phosphorylates HDAC3 for NF-κB acetylation to ameliorate colitis-associated colorectal carcinoma and sepsis

Zhang

Feng

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…SRC is a non-receptor tyrosine kinase family member with a crucial role in tumor progression. PP-2, an inhibitor of SRC, may signi cantly ameliorate the invasiveness of breast cancer cells and enhance the radiosensitivity of glioma cells [45,46]. Moreover, in our study, PP-2 showed therapeutic value in six HPVnegative HNSCC cell lines in vitro.…”

Section: Discussionsupporting

confidence: 56%

Identification of Four Key Prognostic Genes and Three Potential Drugs in Human Papillomavirus Negative Head and Neck Squamous Cell Carcinoma

Tian

Zhang

et al. 2020

Preprint

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BackgroundHead and neck squamous cell carcinoma (HNSCC) is a common tumor worldwide with poor prognosis. The pathogenesis of human papillomavirus (HPV)-positive and HPV-negative HNSCCs differs. However, few studies have considered the HPV status when identifying biomarkers for HNSCC. Thus, the identification of biomarkers for HPV-positive and HPV-negative HNSCCs is urgently needed.MethodsThree microarray datasets from Gene Expression Omnibus (GEO) were analyzed, and the differentially expressed genes (DEGs) were obtained. Then, functional enrichment pathway analysis was performed and protein-protein interaction (PPI) networks were constructed. The expression of hub genes at both the mRNA and protein level was determined in Oncomine, The Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA). In addition, survival analysis of the patient stratified by HPV status and the expression levels of key genes were performed based on TCGA data. The role of AREG, STAG3, CAV1 and C19orf57 in cancer were analyzed through Gene set enrichment analysis (GSEA). Finally, the top ten small molecule drugs were identified and the therapeutic value of zonisamide, NVP-AUY922, PP-2 and fostamatinib was further evaluated in six HPV-negative HNSCC cell lines.ResultsIn total, 47 DEGs were obtained, 11 of which were identified as hub genes. Biological process analysis indicated that the hub genes were associated with the G1/S transition of the mitotic cell cycle. Survival analysis uncovered that the prognostic value of AREG, STAG3, C19orf57 and CAV1 differed between HPV-positive and HPV-negative patients. Gene set enrichment analysis (GSEA) showed the role of AREG, STAG3 and CAV1 in dysregulated pathways of tumor. Ten small molecules were identified as potential drugs specifically for HPV-positive or HPV-negative patients; three—NVP-AUY922, fostamatinib and PP-2—greatly inhibited the proliferation of six HPV-negative HNSCC cell lines in vitro, and NVP-AUY922 inhibited three HPV-negative HNSCC xenografts in vivo.ConclusionsIn conclusion, AREG, STAG3, C19orf57 and CAV1 are key prognostic factors and potential therapeutic targets in HPV-negative HNSCC. NVP-AUY922, fostamatinib and PP-2 may be effective drugs for HPV-negative HNSCC.

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“…Thus, Src acts as an important oncogenic switch linked to the activity of growth factors receptors, including EGFR and HER2 [63]. Indeed, Src activation is a critical event in the signaling downstream EGFR during breast cancer progression, stimulating migration and invasion of surrounding tissues [64]. Several preclinical studies have successfully used an Src inhibitor in order to counteract the aggressive phenotype of HER2+ breast cancer lines.…”

Section: Breast Cancermentioning

confidence: 99%

Src Family Kinases as Therapeutic Targets in Advanced Solid Tumors: What We Have Learned So Far

Martellucci

Clementi

Sabetta

et al. 2020

Cancers

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Src is the prototypal member of Src Family tyrosine Kinases (SFKs), a large non-receptor kinase class that controls multiple signaling pathways in animal cells. SFKs activation is necessary for the mitogenic signal from many growth factors, but also for the acquisition of migratory and invasive phenotype. Indeed, oncogenic activation of SFKs has been demonstrated to play an important role in solid cancers; promoting tumor growth and formation of distant metastases. Several drugs targeting SFKs have been developed and tested in preclinical models and many of them have successfully reached clinical use in hematologic cancers. Although in solid tumors SFKs inhibitors have consistently confirmed their ability in blocking cancer cell progression in several experimental models; their utilization in clinical trials has unveiled unexpected complications against an effective utilization in patients. In this review, we summarize basic molecular mechanisms involving SFKs in cancer spreading and metastasization; and discuss preclinical and clinical data highlighting the main challenges for their future application as therapeutic targets in solid cancer progression

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EGFR–c-Src-Mediated HDAC3 Phosphorylation Exacerbates Invasion of Breast Cancer Cells

Cited by 20 publications

References 50 publications

HIPK2 phosphorylates HDAC3 for NF-κB acetylation to ameliorate colitis-associated colorectal carcinoma and sepsis

HIPK2 phosphorylates HDAC3 for NF-κB acetylation to ameliorate colitis-associated colorectal carcinoma and sepsis

Identification of Four Key Prognostic Genes and Three Potential Drugs in Human Papillomavirus Negative Head and Neck Squamous Cell Carcinoma

Src Family Kinases as Therapeutic Targets in Advanced Solid Tumors: What We Have Learned So Far

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