SHP and Sin3A expression are essential for adamantyl-substituted retinoid-related molecule–mediated nuclear factor-κB activation, c-Fos/c-Jun expression, and cellular apoptosis

Farhana, Lulu; Dawson, Marcia I.; Xu, Liping; Fontana, Joseph A.

doi:10.1158/1535-7163.mct-08-0964

Cited by 27 publications

(27 citation statements)

References 42 publications

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“…We show that ING2 sumoylation enhances its association with Sin3A. Sin3A is a stable component of the Sin3A/HDAC chromatin-modifying complex and is thus involved not only in the repression but also in the activation of a large number of genes (Dannenberg et al, 2005;Farhana et al, 2009). ING2 and Sin3A were previously shown to associate to regulate gene expressions (Shi et al, 2006).…”

Section: Ing2 Sumoylation and Sin3a Mediate Gene Expressionmentioning

confidence: 87%

Sumoylation of ING2 regulates the transcription mediated by Sin3A

et al. 2010

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ING2 (inhibitor of growth 2) is a candidate tumorsuppressor gene involved in cell cycle control, apoptosis and senescence. Although the functions of ING2 within the chromatin remodeling complex Sin3A/histone deacetylase (HDAC) and in the p53 pathway have been described, how ING2 itself is regulated remains unknown. In this study we report for the first time that ING2 can be sumoylated by small ubiquitin-like modifier 1 (SUMO1) on lysine 195 both in vitro and in vivo. Strikingly, ING2 sumoylation enhances its association with Sin3a. We provide evidences that ING2 can bind to the promoter of genes to mediate their expression and that sumoylation of ING2 is required for this binding to some of these genes. Among them, we identified the gene TMEM71 (transmembrane protein 71), whose expression is regulated by ING2 sumoylation. ING2 must be sumoylated to bind to the promoter of TMEM71 and to recruit the Sin3A chromatin-modifying complex to this promoter, in order to regulate TMEM71 transcription. Hence, sumoylation of ING2 enhances its binding to the Sin3A/HDAC complex and is required to regulate gene transcriptions.

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Section: Ing2 Sumoylation and Sin3a Mediate Gene Expressionmentioning

confidence: 87%

Sumoylation of ING2 regulates the transcription mediated by Sin3A

et al. 2010

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“…Although ARRs were initially synthesized to demonstrate selectivity in the activation of retinoid nuclear receptor (RAR) subtypes, they have been shown to inhibit growth and induce apoptosis in different malignant cell types independent of RAR and retinoid x receptor (RXR) activation and function [30–34]. We found that Ras wild type and mutant pancreatic cancer cell lines COLO357, PANC-1, Capan-2, AsPc-1 cells, and MiaPaCa-2 display significant sensitivity to AHP3- and 3-Cl-AHPC-mediated growth inhibition and apoptosis induction.…”

Section: Discussionmentioning

confidence: 99%

“…The ability of the ARRs to enhance or inhibit the expression of a number of genes and proteins has been demonstrated [30–35]. We have found that both 3-Cl-AHPC and AHP3 significantly decreased IGF-1R and β -catenin expression and that the decreased expression of IGF-1R and β -catenin inhibited the growth and enhanced apoptosis of the pancreatic cancer cells suggesting that decreased IGF-1R and β -catenin expression potentiates ARR-mediated apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Adamantyl Retinoid-Related Molecules Induce Apoptosis in Pancreatic Cancer Cells by Inhibiting IGF-1R and Wnt/β-Catenin Pathways

Farhana

Dawson

Das

et al. 2012

Journal of Oncology

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Pancreatic carcinoma has a dismal prognosis as it often presents as locally advanced or metastatic. We have found that exposure to adamantyl-substituted retinoid-related (ARR) compounds 3-Cl-AHPC and AHP3 resulted in growth inhibition and apoptosis induction in PANC-1, Capan-2, and MiaPaCa-2 pancreatic cancer cell lines. In addition, AHP3 and 3-Cl-AHPC inhibited growth and induced apoptosis in spheres derived from the CD44+/CD24+(CD133+/EpCAM+) stem-like cell population isolated from the pancreatic cancer cell lines. 3-Cl-AHPC-induced apoptosis was preceded by decreasing expression of IGF-1R, cyclin D1,β-catenin, and activated Notch-1 in the pancreatic cancer cell lines. Decreased IGF-1R expression inhibited PANC-1 proliferation, enhanced 3-Cl-AHPC-mediated apoptosis, and significantly decreased sphere formation. 3-Cl-AHPC inhibited the Wnt/β-catenin pathway as indicated by decreasedβ-catenin nuclear localization and inhibited Wnt/β-catenin activation of transcription factor TCF/LEF. Knockdown ofβ-catenin using sh-RNA also induced apoptosis and inhibited growth in pancreatic cancer cells. Thus, 3-Cl-AHPC and AHP3 induce apoptosis in pancreatic cancer cells and cancer stem-like cells and may serve as an important potential therapeutic agent in the treatment of pancreatic cancer.

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“…Nevertheless, the loss of SHP or Sin3A expression had little effect on ARR inhibition of cellular proliferation, suggesting that ARR mediated growth inhibition and apoptosis seem to involve separate pathways [48]. Continued study showed that induction of c-Fos and c-Jun expression as well as NF-kappaB activation by ARRs were SHP-dependent and may be essential for ARR mediated apoptosis [45]. A more recent in vivo and in vitro study found that the human acute myelogenous leukemia cell line FFMA-AML and TF (v-SRC) cells displayed resistance to standard retinoid (including trans-retinoic acid, 9-cis-retinoic acid, and the synthetic retinoid TTNPB) induced apoptosis but showed sensitivity to 3-Cl-AHPC and AHPN mediated apoptosis.…”

Section: Shp and Apoptosismentioning

confidence: 99%

Nuclear Receptor Small Heterodimer Partner in Apoptosis Signaling and Liver Cancer

Zhang

Wang

2011

Cancers

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Small heterodimer partner (SHP, NR0B2) is a unique orphan nuclear receptor that contains the dimerization and a putative ligand-binding domain, but lacks the conserved DNA binding domain. SHP exerts its physiological function as an inhibitor of gene transcription through physical interaction with multiple nuclear receptors and transcriptional factors. SHP is a critical transcriptional regulator affecting diverse biological functions, including bile acid, cholesterol and lipid metabolism, glucose and energy homeostasis, and reproductive biology. Recently, we and others have demonstrated that SHP is an epigenetically regulated transcriptional repressor that suppresses the development of liver cancer. In this review, we summarize recent major findings regarding the role of SHP in cell proliferation, apoptosis, and DNA methylation, and discuss recent progress in understanding the function of SHP as a tumor suppressor in the development of liver cancer. Future study will be focused on identifying SHP associated novel prooncogenes and anti-oncogenes in liver cancer progression and applying the knowledge gained on SHP in liver cancer prevention, diagnosis and treatment.

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SHP and Sin3A expression are essential for adamantyl-substituted retinoid-related molecule–mediated nuclear factor-κB activation, c-Fos/c-Jun expression, and cellular apoptosis

Abstract: We previously found that the adamantyl-substituted retinoid-related molecules bind to the small heterodimer partner (SHP) as well as the Sin3A complex. In this report, we delineated the role of SHP and the Sin3A complex in 4-[3′-

Cited by 27 publications

References 42 publications

Sumoylation of ING2 regulates the transcription mediated by Sin3A

Sumoylation of ING2 regulates the transcription mediated by Sin3A

Adamantyl Retinoid-Related Molecules Induce Apoptosis in Pancreatic Cancer Cells by Inhibiting IGF-1R and Wnt/β-Catenin Pathways

Nuclear Receptor Small Heterodimer Partner in Apoptosis Signaling and Liver Cancer

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