Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

Puca, Rosa; Nardinocchi, Lavinia; Givol, David; D’Orazi, Gabriella

doi:10.1038/onc.2010.183

Cited by 131 publications

(132 citation statements)

References 97 publications

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“…Our data fit this model and extend it by providing evidence that the potent oncogene MYCN induces DDR and leads to stabilization of both p53 and HIPK2, as indicated by ATM and NBS1 RNAi experiments. Interestingly, both HIPK2 and p53 S46 phosphorylation have also been involved in cellular senescence (47,48) and mouse embryo fibroblasts bearing a human mutant knock-in p53 nonphosphorylatable at p53 S46 escape from oncogene-induced senescence (49). Together with our present data, these observations support the speculation that oncogenes might induce apoptosis and/ or cell senescence due to the contemporary accumulation of both p53 and its proapoptotic/senescence activator HIPK2, via DDR.…”

Section: Discussionsupporting

confidence: 80%

MYCN Sensitizes Human Neuroblastoma to Apoptosis by HIPK2 Activation through a DNA Damage Response

Petroni

Veschi

Prodosmo

et al. 2011

Molecular Cancer Research

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MYCN amplification occurs in approximately 20% of human neuroblastomas and is associated with early tumor progression and poor outcome, despite intensive multimodal treatment. However, MYCN overexpression also sensitizes neuroblastoma cells to apoptosis. Thus, uncovering the molecular mechanisms linking MYCN to apoptosis might contribute to designing more efficient therapies for MYCN-amplified tumors. Here we show that MYCN-dependent sensitization to apoptosis requires activation of p53 and its phosphorylation at serine 46. The p53 S46 kinase HIPK2 accumulates on MYCN expression, and its depletion by RNA interference impairs p53 S46 phosphorylation and apoptosis. Remarkably, MYCN induces a DNA damage response that accounts for the inhibition of HIPK2 degradation through an ATM-and NBS1-dependent pathway. Prompted by the rare occurrence of p53 mutations and by the broad expression of HIPK2 in our human neuroblastoma series, we evaluated the effects of the p53-reactivating compound Nutlin-3 on this pathway. At variance from other tumor histotypes, in MYCN-amplified neuroblastoma, Nutlin-3 further induced HIPK2 accumulation, p53 S46 phosphorylation, and apoptosis, and in combination with clastogenic agents purged virtually the entire cell population. Altogether, our data uncover a novel mechanism linking MYCN to apoptosis that can be triggered by the p53-reactivating compound Nutlin-3, supporting its use in the most difficult-to-treat subset of neuroblastoma.

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Section: Discussionsupporting

confidence: 80%

MYCN Sensitizes Human Neuroblastoma to Apoptosis by HIPK2 Activation through a DNA Damage Response

Petroni

Veschi

Prodosmo

et al. 2011

Molecular Cancer Research

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“…11 Inhibition of HIF-1a activity by HIPK2 reduces MDR1 gene expression and restrains HIF-1-induced tumor chemoresistance. 12 Despite the extensive knowledge on HIPK2 function in many tumors, 34 there are no reports about the role of HIPK2 in GC. Unexpectedly, in contrast to its tumor suppressor role, elevated levels of HIPK2 mRNA were observed in PD patients showing a lower expression of both miR-27a and miR-181a.…”

Section: Discussionmentioning

confidence: 99%

Role of miR-27a, miR-181a and miR-20b in gastric cancer hypoxia-induced chemoresistance

Danza

Silvestris

Simone

et al. 2016

Cancer Biology & Therapy

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Despite the search for new therapeutic strategies for gastric cancer (GC), there is much evidence of progression due to resistance to chemotherapy. Multidrug resistance (MDR) is the ability of cancer cells to survive after exposure to chemotherapeutic agents. The involvement of miRNAs in the development of MDR has been well described but miRNAs able to modulate the sensitivity to chemotherapy by regulating hypoxia signaling pathways have not yet been fully addressed in GC. Our aim was to analyze miR-20b, miR-27a and miR-181a expression with respect to (epirubicin/oxaliplatin/capecitabine (EOX)) chemotherapy regimen in a set of GC patients, in order to investigate whether miRNAs deregulation may influence GC MDR also via hypoxia signaling modulation. Cancer biopsy were obtained from 21 untreated HER2 negative advanced GC patients, retrospectively analyzed. All patients received a first-line chemotherapy (EOX) regimen. MirWalk database was used to identify miR-27a, miR-181a and miR-20b target genes. The expression of miRNAs and of HIPK2, HIF1A and MDR1 genes were detected by real-time PCR. HIPK2 localization was assessed by immunohistochemistry. Our data showed the down-regulation of miR-20b, miR-27a, miR-181a concomitantly to higher levels of MDR1, HIF1A and HIPK2 genes in GC patients with a progressive disease respect to those with a disease control rate. Moreover, immunohistochemistry assay highlighted a higher cytoplasmic HIPK2 staining, suggesting a different role for it. We showed that aberrant expression of miR-20b, miR27a and miR-181a was associated with chemotherapeutic response in GC through HIF1A, MDR1 and HIPK2 genes modulation, suggesting a possible novel therapeutic strategy.

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“…HIPK2 was shown to bind p53 and differentially regulate its localization, phosphorylation, acetylation and transcriptional activity, depending on the extent of the damage. In particular, upon severe, presumably irreparable DNA damage induced by lethal doses of UV, CDDP or DOX, HIPK2 is strongly upregulated and phosphorylates human p53 at S46 (Puca et al, 2010), an apoptosisspecific p53 posttranslational modification (Oda et al, 2000) or its mouse ortholog at S58 (Cecchinelli et al, 2006b). In contrast, in less severe, presumably reparable DNA damage conditions induced by sub-lethal doses of UV or DOX, HIPK2 is ubiquitylated by MDM2 in a p53 dependent manner and targeted to proteasomal degradation (Rinaldo et al, 2007a).…”

Section: Introductionmentioning

confidence: 97%

“…Besides p53 phosphorylation, HIPK2 promotes apoptosis by modulating other factors, directly or indirectly related to p53-mediated apoptosis, such as the b-catenin regulator Axin, the p53 family member p73, the p53 inhibitor MDM2, the acetyl transferases p300/CPB and PCaF (Rinaldo et al, 2007b;Li et al, 2009;Puca et al, 2010), and, more recently, PML (Gresko et al, 2009) and the methyl-CpG-binding protein 2 (Bracaglia et al, 2009). In addition, HIPK2 depletion in human tumor cells was shown to induce p53 misfolding, yielding a 'mutant-like' p53 conformation and resistance to DOX and CDDP (Puca et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

HIPK2 phosphorylates ΔNp63α and promotes its degradation in response to DNA damage

Lazzari¹,

Prodosmo²,

Siepi³

et al. 2011

Oncogene

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Homeodomain-interacting protein kinase 2 (HIPK2) is an emerging player in cell response to genotoxic agents that senses damage intensity and contributes to the cell's choice between cell cycle arrest and apoptosis. Phosphorylation of p53 at S46, an apoptosis-specific p53 posttranslational modification, is the most characterized HIPK2 function in response to lethal doses of ultraviolet (UV), ionizing radiation or different anticancer drugs, such as cisplatin, roscovitine and doxorubicin (DOX). Indeed, like p53, HIPK2 has been shown to contribute to the effectiveness of these treatments. Interestingly, p53-independent mechanisms of HIPK2-induced apoptosis were described for UV and tumor growth factor-b treatments; however, it is unknown whether these mechanisms are relevant for the responses to anticancer drugs. Because of the importance of the so-called 'p53-independent apoptosis and drug response' in human cancer chemotherapy, we asked whether p53-independent factor(s) might be involved in HIPK2-mediated chemosensitivity. Here, we show that HIPK2 depletion by RNA interference induces resistance to different anticancer drugs even in p53-null cells, suggesting the involvement of HIPK2 targets other than p53 in response to chemotherapy. In particular, we found that HIPK2 phosphorylates and promotes proteasomal degradation of DNp63a, a prosurvival DN isoform of the p53 family member, p63. Indeed, effective cell response to different genotoxic agents was shown to require phosphorylation-induced proteasomal degradation of DNp63a. In DOX-treated cells, we show that HIPK2 depletion interferes with DNp63a degradation, and expression of a HIPK2-resistant DNp63a-D390 mutant induces chemoresistance. We identify T397 as the DNp63a residue phosphorylated by HIPK2, and show that the nonphosphorylatable DNp63a-T397A mutant is not degraded in the face of either HIPK2 overexpression or DOX treatment. These results indicate DNp63a as a novel target of HIPK2 in response to genotoxic drugs.

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Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

Cited by 131 publications

References 97 publications

MYCN Sensitizes Human Neuroblastoma to Apoptosis by HIPK2 Activation through a DNA Damage Response

MYCN Sensitizes Human Neuroblastoma to Apoptosis by HIPK2 Activation through a DNA Damage Response

Role of miR-27a, miR-181a and miR-20b in gastric cancer hypoxia-induced chemoresistance

HIPK2 phosphorylates ΔNp63α and promotes its degradation in response to DNA damage

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