Identification of p21 (CIP1/WAF1) as a direct target gene of HIC1 (Hypermethylated In Cancer 1)

Dehennaut, Vanessa; Loison, Ingrid; Boulay, Gaylor; Rechem, Capucine Van; Leprince, Dominique

doi:10.1016/j.bbrc.2012.11.045

Cited by 18 publications

(16 citation statements)

References 24 publications

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“…Although the portion of p53-positive cells was decreased in Hic1 À/À neoplastic tissues, it is unlikely that the increased tumor size observed upon Hic1 deletion is linked to the attenuated p53-mediated response. In human cells, HIC1 directly represses transcription of the CDKN1A gene encoding p21 (33). Strikingly, in Hic1-deficient tumors, we observed the opposite effect of Hic1 absence, that is, reduced p21 staining (Fig.…”

Section: Discussionmentioning

confidence: 72%

“…In addition, increased expression of previously identified HIC1 target genes cyclin-dependent kinase inhibitor 1a (CDKN1A; ref. 33), Sox9 (13), and Sirt1 (7) was observed, but these genes did not satisfy the significance criteria (not shown). Rather unexpectedly, the GSEA analysis using the Enricher gene library online tool (24) revealed that the inactivation of the Hic1 gene in MEFs mainly altered expression of genes involved in lipid metabolism (Supplementary Table S3).…”

Section: Identification Of Tlr2 As a Novel Target Gene Repressed By Hmentioning

confidence: 99%

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HIC1 Tumor Suppressor Loss Potentiates TLR2/NF-κB Signaling and Promotes Tissue Damage–Associated Tumorigenesis

Janečková

Pospíchalová

Fafílek

et al. 2015

Molecular Cancer Research

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Section: Discussionmentioning

confidence: 72%

Section: Identification Of Tlr2 As a Novel Target Gene Repressed By Hmentioning

confidence: 99%

HIC1 Tumor Suppressor Loss Potentiates TLR2/NF-κB Signaling and Promotes Tissue Damage–Associated Tumorigenesis

Janečková

Pospíchalová

Fafílek

et al. 2015

Molecular Cancer Research

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“…Expression of HIC1 is silenced in TNBC Increasing evidence indicates that HIC1 is silenced by epigenetic modifications in many types of prevalent human tumors (11)(12)(13)(14)24). We and other groups recently described the role of HIC1 in tumor progression as partially relying on a variety of downstream targets (11)(12)(13)(14)24).…”

Section: Resultsmentioning

confidence: 99%

“…We and other groups recently described the role of HIC1 in tumor progression as partially relying on a variety of downstream targets (11)(12)(13)(14)24). However, the role and regulatory mechanism of HIC1 in different molecular subtypes of breast cancer remain unclear.…”

Section: Resultsmentioning

confidence: 99%

HIC1 Silencing in Triple-Negative Breast Cancer Drives Progression through Misregulation of LCN2

et al. 2014

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The tumor suppressor gene HIC1 is frequently deleted or epigenetically silenced in human cancer, where its restoration may improve cancer prognosis. Here, we report results illuminating how HIC1 silencing alters effect or signals in triple-negative breast cancer (TNBC), which are crucial for its pathogenesis. HIC1 expression was silenced only in TNBC compared with other molecular subtypes of breast cancer. Restoring HIC1 expression in TNBC cells reduced cell migration, invasion, and metastasis, whereas RNAi-mediated silencing of HIC1 in untransformed human breast cells increased their invasive capabilities. Mechanistic investigations identified the small-secreted protein lipocalin-2 (LCN2), as a critical downstream target of HIC1 in TNBC cells. Elevating LCN2 expression in cells expressing HIC1 partially rescued its suppression of cell invasion and metastasis. Notably, autocrine secretion of LCN2 induced by loss of HIC1 activated the AKT pathway through the neutrophil gelatinase-associated lipocalin receptor, which is associated with TNBC progression. Taken together, our findings revealed that the HIC1-LCN2 axis may serve as a subtype-specific prognostic biomarker, providing an appealing candidate target for TNBC therapy. Cancer Res; 74(3); 862-72. Ó2013 AACR.

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“…To address this issue, we first performed a pilot time-course response of BJ-hTert fibroblasts to etoposide. BJ-hTERT cells transfected with Control siRNAs or HIC1 siRNAs were treated with etoposide for 1, 6 and 16 hours and analyzed by Western blot for expression of the cell cycle inhibitor P21 CIP1 which is a key factor mediating the P53 response and also a direct target gene of HIC1 [25]. A similar induction of P21 CIP1 expression is observed after either 6- or 16- hour etoposide treatments as well as a further increase in siHIC1-treated cells as expected for a HIC1 direct target gene (Supplementary Figure S5A).…”

Section: Resultsmentioning

confidence: 99%

HIC1 (hypermethylated in cancer 1) SUMOylation is dispensable for DNA repair but is essential for the apoptotic DNA damage response (DDR) to irreparable DNA double-strand breaks (DSBs)

et al. 2016

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The tumor suppressor gene HIC1 (Hypermethylated In Cancer 1) encodes a transcriptional repressor mediating the p53-dependent apoptotic response to irreparable DNA double-strand breaks (DSBs) through direct transcriptional repression of SIRT1. HIC1 is also essential for DSB repair as silencing of endogenous HIC1 in BJ-hTERT fibroblasts significantly delays DNA repair in functional Comet assays. HIC1 SUMOylation favours its interaction with MTA1, a component of NuRD complexes. In contrast with irreparable DSBs induced by 16-hours of etoposide treatment, we show that repairable DSBs induced by 1 h etoposide treatment do not increase HIC1 SUMOylation or its interaction with MTA1. Furthermore, HIC1 SUMOylation is dispensable for DNA repair since the non-SUMOylatable E316A mutant is as efficient as wt HIC1 in Comet assays. Upon induction of irreparable DSBs, the ATM-mediated increase of HIC1 SUMOylation is independent of its effector kinase Chk2. Moreover, irreparable DSBs strongly increase both the interaction of HIC1 with MTA1 and MTA3 and their binding to the SIRT1 promoter. To characterize the molecular mechanisms sustained by this increased repression potential, we established global expression profiles of BJ-hTERT fibroblasts transfected with HIC1-siRNA or control siRNA and treated or not with etoposide. We identified 475 genes potentially repressed by HIC1 with cell death and cell cycle as the main cellular functions identified by pathway analysis. Among them, CXCL12, EPHA4, TGFβR3 and TRIB2, also known as MTA1 target-genes, were validated by qRT-PCR analyses. Thus, our data demonstrate that HIC1 SUMOylation is important for the transcriptional response to non-repairable DSBs but dispensable for DNA repair.

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Identification of p21 (CIP1/WAF1) as a direct target gene of HIC1 (Hypermethylated In Cancer 1)

Cited by 18 publications

References 24 publications

HIC1 Tumor Suppressor Loss Potentiates TLR2/NF-κB Signaling and Promotes Tissue Damage–Associated Tumorigenesis

HIC1 Tumor Suppressor Loss Potentiates TLR2/NF-κB Signaling and Promotes Tissue Damage–Associated Tumorigenesis

HIC1 Silencing in Triple-Negative Breast Cancer Drives Progression through Misregulation of LCN2

HIC1 (hypermethylated in cancer 1) SUMOylation is dispensable for DNA repair but is essential for the apoptotic DNA damage response (DDR) to irreparable DNA double-strand breaks (DSBs)

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