HDAC4 Levels Control Sensibility toward Cisplatin in Gastric Cancer via the p53-p73/BIK Pathway

Spaety, Marie-Élodie; Gries, Alexandre; Badie, Amandine; Venkatasamy, Aïna; Romain, B.; Orvain, Christophe; Yanagihara, Kazuyoshi; Okamoto, Koji; Jung, Alain C.; Mellitzer, Georg; Pfeffer, Sébastien; Gaiddon, Christian

doi:10.3390/cancers11111747

Cited by 32 publications

(31 citation statements)

References 53 publications

(61 reference statements)

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“…The study from Christian Gaiddon's Lab showed that HDAC significantly induces the mRNA and protein levels of TAp73 and p53 on the protein level in gastric cancer cell lines after cisplatin treatment. This leads to the efficient induction of the proapoptotic gene PMAIP1 (NOXA) and BIK [113]. These findings support the key role of TAp73 in eliminating cancer cells in response to cisplatin.…”

Section: Pharmacological Reactivation Of P73supporting

confidence: 66%

The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy - Drug Repurposing

Zawacka-Pankau

2020

Preprint

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p53 and p73 are critical tumor suppressors often inactivated in human cancers through various mechanisms. Owing to high structural homology, the proteins have many common functions and recognize the same set of genes involved in apoptosis and cell cycle regulation. p53 is known as the ‘guardian of the genome’ and together with p73 form a barrier against cancer development and progression. The TP53 is mutated in more than 50% of all human cancers and the germline mutations in TP53 predispose to the early onset of multiple tumors in Li-Fraumeni Syndrome (LFS), the inherited cancer predisposition. In cancers where TP53 gene is intact, p53 is degraded. Despite the ongoing efforts, the treatment of cancers remains challenging. This is due to late diagnoses, the toxicity of current standard of care and marginal benefit of newly approved therapies. Presently, the endeavours focus on reactivating p53 exclusively, neglecting the potential of the restoration of p73 protein for cancer eradication. Taken that several small molecules reactivating p53 failed in clinical trials, there is a need to develop new treatments targeting p53 proteins in cancer. This review outlines the most advanced strategies to reactivate p53 and p73 and describes drug repurposing approaches for the efficient reinstatement of the p53 proteins for cancer therapy.

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Section: Pharmacological Reactivation Of P73supporting

confidence: 66%

The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy - Drug Repurposing

Zawacka-Pankau

2020

Preprint

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“…Hence, more selective inhibitors have been developed. For instance, HDAC4 has an elevated expression in GC, and its alteration (mutation or deletion) correlates with a better prognosis [ 343 ]. The inhibition of HDAC4 by small chemicals enhances cisplatin-induced apoptosis in vitro and in vivo.…”

Section: Tp53 a Guardian Against Gastric Cancmentioning

confidence: 99%

Isoforms of the p53 Family and Gastric Cancer: A Ménage à Trois for an Unfinished Affair

Blanchet

Bourgmayer

Kurtz

et al. 2021

Cancers

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Gastric cancer is one of the most aggressive cancers, with a median survival of 12 months. This illustrates its complexity and the lack of therapeutic options, such as personalized therapy, because predictive markers do not exist. Thus, gastric cancer remains mostly treated with cytotoxic chemotherapies. In addition, less than 20% of patients respond to immunotherapy. TP53 mutations are particularly frequent in gastric cancer (±50% and up to 70% in metastatic) and are considered an early event in the tumorigenic process. Alterations in the expression of other members of the p53 family, i.e., p63 and p73, have also been described. In this context, the role of the members of the p53 family and their isoforms have been investigated over the years, resulting in conflicting data. For instance, whether mutations of TP53 or the dysregulation of its homologs may represent biomarkers for aggressivity or response to therapy still remains a matter of debate. This uncertainty illustrates the lack of information on the molecular pathways involving the p53 family in gastric cancer. In this review, we summarize and discuss the most relevant molecular and clinical data on the role of the p53 family in gastric cancer and enumerate potential therapeutic innovative strategies.

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“…The study from Christian Gaiddon’s Lab showed that HDAC significantly induces mRNA and protein levels of p73 and protein levels of p53 in gastric cancer cell lines after cisplatin treatment. This leads to the efficient induction of the proapoptotic genes PMAIP 1 ( NOXA ) and BIK [ 113 ]. These findings support the key role of TAp73 in eliminating cancer cells in response to cisplatin and delineate p73 as a vital target of the drug.…”

Section: Structure and Tumor Suppressor Function Of P53 And P73mentioning

confidence: 99%

The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy-Drug Repurposing

Zawacka-Pankau

2020

Cancers

View full text Add to dashboard Cite

p53 and p73 are critical tumor suppressors that are often inactivated in human cancers through various mechanisms. Owing to their high structural homology, the proteins have many joined functions and recognize the same set of genes involved in apoptosis and cell cycle regulation. p53 is known as the ‘guardian of the genome’ and together with p73 forms a barrier against cancer development and progression. The TP53 is mutated in more than 50% of all human cancers and the germline mutations in TP53 predispose to the early onset of multiple tumors in Li–Fraumeni syndrome (LFS), the inherited cancer predisposition. In cancers where TP53 gene is intact, p53 is degraded. Despite the ongoing efforts, the treatment of cancers remains challenging. This is due to late diagnoses, the toxicity of the current standard of care and marginal benefit of newly approved therapies. Presently, the endeavors focus on reactivating p53 exclusively, neglecting the potential of the restoration of p73 protein for cancer eradication. Taken that several small molecules reactivating p53 failed in clinical trials, there is a need to develop new treatments targeting p53 proteins in cancer. This review outlines the most advanced strategies to reactivate p53 and p73 and describes drug repurposing approaches for the efficient reinstatement of the p53 proteins for cancer therapy.

show abstract

HDAC4 Levels Control Sensibility toward Cisplatin in Gastric Cancer via the p53-p73/BIK Pathway

Cited by 32 publications

References 53 publications

The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy - Drug Repurposing

The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy - Drug Repurposing

Isoforms of the p53 Family and Gastric Cancer: A Ménage à Trois for an Unfinished Affair

The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy-Drug Repurposing

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