Src Regulates the Activity of the ING1 Tumor Suppressor

Yu, Lisa; Thakur, Satbir; Leong-Quong, Rebecca Y. Y.; Suzuki, Keiko; Pang, Andy; Bjorge, Jeffrey D.; Riabowol, Karl; Fujita, Daishi

doi:10.1371/journal.pone.0060943

Cited by 21 publications

(16 citation statements)

References 51 publications

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“…al. reported that Src phosphorylated the HDAC Inhibitor of Growth 1 (ING1), resulting in nuclear to cytoplasmic localization and decrease in protein stability (44) . C-terminal Src kinase (Csk)-binding protein (Cbp)/PAG1 expression was repressed via Src-mediated alterations in histone H4 acetylation and trimethylation of histone H3/lysine 27 in the Cbp promoter and associated changes in HDAC activity (45).…”

Section: Discussionmentioning

confidence: 99%

Dual Src Kinase/Pretubulin Inhibitor KX-01, Sensitizes ERα-negative Breast Cancers to Tamoxifen through ERα Reexpression

Anbalagan

Sheng

Fleischer

et al. 2017

Molecular Cancer Research

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Unlike breast cancer that is positive for estrogen receptor-α (ERα), there are no targeted therapies for triple negative breast cancer (TNBC). ERα is silenced in TNBC through epigenetic changes including DNA methylation and histone acetylation. Restoring ERα expression in TNBC may sensitize patients to endocrine therapy. Expression of c-Src and ERα are inversely correlated in breast cancer suggesting that c-Src inhibition may lead to re-expression of ERα in TNBC. KX-01 is a peptide substrate-targeted Src/pretubulin inhibitor in clinical trials for solid tumors. KX-01 (1 mg/kg body weight-BID) inhibited growth of tamoxifen-resistant MDA-MB-231 and MDA-MB-157 TNBC xenografts in NUDE mice that was correlated with Src kinase inhibition. KX-01 also increased ERα mRNA and protein, as well as increased the ERα targets progesterone receptor (PR), pS2 (TFF1), cyclin D1 (CCND1) and c-myc (MYC) in MDA-MB-231 and MDA-MB-468 but not MDA-MB-157 xenografts. MDA-MB-231 and MDA-MB-468 tumors exhibited reduction in mesenchymal markers (vimentin, β-catenin) and increase in epithelial marker (E-cadherin) suggesting mesenchymal-to-epithelial transition (MET). KX-01 sensitized MDA-MB-231 and MDA-MB-468 tumors to tamoxifen growth inhibition and tamoxifen repression of the ERα targets pS2, cyclin D1 and c-myc. Chromatin immunoprecipitation (ChIP) of the ERα promoter in KX-01 treated tumors demonstrated enrichment of active transcription marks (acetyl-H3, acetyl-H3Lys9), dissociation of HDAC1, and recruitment of RNA polymerase II. Methylation-specific PCR and bisulfite sequencing demonstrated no alteration in ERα promoter methylation by KX-01. These data demonstrate that in addition to Src kinase inhibition, peptidomimetic KX-01 restores ERα expression in TNBC through changes in histone acetylation that sensitize tumors to tamoxifen. Implications: Src kinase/pretubulin inhibitor KX-01 restores functional ERα expression in ERα- breast tumors, a novel treatment strategy to treat triple-negative breast cancer.

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Section: Discussionmentioning

confidence: 99%

Dual Src Kinase/Pretubulin Inhibitor KX-01, Sensitizes ERα-negative Breast Cancers to Tamoxifen through ERα Reexpression

Anbalagan

Sheng

Fleischer

et al. 2017

Molecular Cancer Research

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“…Zhang et al (17) demonstrated that immunostaining for ING2 was mostly located to the cytoplasm, while weak nuclear staining was also observed in HCC tissues and normal hepatocytes, in line with a study by Gozani et al (5), who reported that phosphatidylinositol 5-phosphate 4-kinase type II β expression decreased endogenous nuclear ING2 in HT1080 fibrosarcoma cells. It has been reported that ING1 phosphorylation by 14-3-3 family members (23) or Src (24) caused its cytoplasmic re-localization leading to apoptotic induction. Future studies should investigate the purpose of ING2 restoration in the cytoplasm as well as its function.…”

Section: Discussionmentioning

confidence: 99%

Expression profiles of inhibitor of growth protein 2 in normal and cancer tissues: An immunohistochemical screening analysis

Zhao

Gou

Lü

et al. 2015

Molecular Medicine Reports

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Inhibitor of growth protein 2 (ING2) has an important role in the regulation of chromatin remodeling, cell proliferation, cell‑cycle arrest, senescence and apoptosis. The present study performed an immunohistochemical analysis for expression profiling of ING2 protein in an array of tissues comprising normal mouse and human tissues, as well as human hepatocellular (n=62), renal clear cell (n=62), pancreatic (n=62), esophageal squamous cell (n=45), cervical squamous cell (n=31), breast (n=144), gastric (n=196), colorectal (n=96), ovarian (n=208), endometrial (n=96) and lung (n=192) carcinoma tissues. In mouse tissues, ING2 was detected in the nuclei and cytoplasm of the glandular epithelium of breast, hepatocytes, intestine, bronchium and alveoli, as well as the squamous epithelium of skin and glomeruli, and in myocardial cells, while it was located in the cytoplasm of renal tubules and striated muscle cells. ING2 protein was scattered in the brain and spleen. In human tissues, ING2 protein was principally distributed in the cytoplasm, while in it was present in the cytoplasm and nuclei in the stomach, intestine, cervix, endometrium trachea, breast and pancreas. The nuclear location of ING2 in the stomach was more prominent than that in the cytoplasm. High ING2 immunoreactivity was detected in the tongue, stomach, skin, pancreas, cervix and breast, whereas weakly in the brain stem, thymus, thyroid, lung, striated muscle, testis, bladder and ovary. In total, 617 out of 1,194 of the tested cancer tissues (51.7%) were ING2-positive. In most cases, ING2 expression was found to be restricted to the cytoplasm of all cancer tissues, while in certain cancer types, including renal clear cell, ovarian and colorectal carcinoma, it was occasionally present in the nuclei. Among the cancer tissues examined, ING2 was most frequently expressed in breast cancer (67.4%) and gynecological cancer types, including ovarian cancer (61.5%) and endometrial cancer (57.3%). Compared with that in the respective normal tissues, ING2 expression in breast cancer tissues was decreased, while that in cervical cancer was upregulated in the nuclei as well as the cytoplasm. In endometrial cancer, expression of ING2 was increased in the nuclei and declined in the cytoplasm compared with that in the normal endometrium. ING2‑positive cases were less frequent for renal clear cell carcinoma (17.7%). The results of the present study suggested that ING2 may be involved in the repair and regeneration of organs or tissues and is associated with breast and gynecological carcinogenesis.

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“…Src destabilizes ING1 by phosphorylation, thereby inducing its export from nucleus. The Src phosphorylation-independent mechanism is based on the capacity of Src to bind directly ING1: in this role as cofactor, Src may prompt the degradation of ING1, or, as an alternative, kinase-dead Src may recruit and/or activate other tyrosine kinases to target this tumor suppressor [56].…”

Section: Src-dependent Regulation Of Tumor Suppressorsmentioning

confidence: 99%

Nuclear Functions of the Tyrosine Kinase Src

Bagnato

Leopizzi²,

Urciuoli

et al. 2020

IJMS

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Src is the representative member of the Src-family kinases (SFKs), a group of tyrosine kinases involved in several cellular processes. Its main function has been for long confined to the plasma membrane/cytoplasm compartment, being a myristoylated protein anchored to the cell membrane and functioning downstream to receptors, most of them lacking intrinsic kinase activity. In the last decades, new roles for some SFKs have been described in the nuclear compartment, suggesting that these proteins can also be involved in directly regulating gene transcription or nucleoskeleton architecture. In this review, we focused on those nuclear functions specifically attributable to Src, by considering its function as both tyrosine kinase and adapting molecule. In particular, we addressed the Src involvement in physiological as well as in pathological conditions, especially in tumors.

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Src Regulates the Activity of the ING1 Tumor Suppressor

Cited by 21 publications

References 51 publications

Dual Src Kinase/Pretubulin Inhibitor KX-01, Sensitizes ERα-negative Breast Cancers to Tamoxifen through ERα Reexpression

Dual Src Kinase/Pretubulin Inhibitor KX-01, Sensitizes ERα-negative Breast Cancers to Tamoxifen through ERα Reexpression

Expression profiles of inhibitor of growth protein 2 in normal and cancer tissues: An immunohistochemical screening analysis

Nuclear Functions of the Tyrosine Kinase Src

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