The tumour suppressor CCDC6 is involved in ROS tolerance and neoplastic transformation by evading ferroptosis

Morra, Francesco; Merolla, Francesco; Marino, Federica Zito; Catalano, Rosaria; Franco, Renato; Chieffi, Paolo; Celetti, Angela

doi:10.1016/j.heliyon.2021.e08399

Cited by 4 publications

(6 citation statements)

References 63 publications

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“…5 , Additional File 10 : Figure S7 D-G). We hypothesized, based on in vitro evidence, that the intensity of the CCDC6 staining could nonetheless predict the response to PARPi, as described in other tumour models [ 36 – 41 ]. However, the CCDC6 staining of PDX cores did not appear sufficient to distinguish a primary sensitive from a resistant tumour or to predict the cisplatin sensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…The PP4c functional role and its involvement in multiple aspects of cellular physiology are emerging [63]. Nevertheless, the CCDC6 ability to interact and modulate the activity of the PP4c complex resulted in relevant responses to genotoxic stress and oxidative stress, highlighting the CCDC6 gene product as a stress key player [36,[63][64][65].…”

Section: Discussionmentioning

confidence: 99%

“…Three drops of Reagent 1 were added into centre of Cytoblock cassette well and spun at 1500 rpm for 5 min. The Cytoblock cassette was processed in a standard tissue processor [ 36 ].…”

Section: Methodsmentioning

confidence: 99%

“…The identification of tumour biomarkers that can predict sensitivity and/or resistance to PARPi as well as further enhance the selective cytotoxicity of such therapeutic drugs is highly envisaged in order to establish an accurate personalised medicine of HGSOC. According to preclinical research, attenuation of CCDC6 in several cancer cell cultures enhances sensitivity to PARPi, which have the ability to work in concert with cisplatin [36][37][38][39][40][41].…”

Section: Ccdc6 Protein Levels Contribute To the Differential Sensitiv...mentioning

confidence: 99%

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The disruption of the CCDC6 – PP4 axis induces a BRCAness like phenotype and sensitivity to PARP inhibitors in high-grade serous ovarian carcinoma

Morra

Merolla

Damia

et al. 2022

J Exp Clin Cancer Res

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Background Treatment with PARP inhibitors (PARPi) is primarily effective against high-grade serous ovarian cancers (HGSOC) with BRCA1/2 mutations or other deficiencies in homologous recombination (HR) repair mechanisms. However, resistance to PARPi frequently develops, mostly as a result of BRCA1/2 reversion mutations. The tumour suppressor CCDC6 is involved in HR repair by regulating the PP4c phosphatase activity on γH2AX. In this work, we reported that in ovarian cancer cells, a physical or functional loss of CCDC6 results synthetic lethal with the PARP-inhibitors drugs, by affecting the HR repair. We also unravelled a role for CCDC6 as predictive marker of PARPi sensitivity in ovarian cancer, and the impact of CCDC6 downregulation in overcoming PARPi resistance in these tumours. Methods A panel of HGSOC cell lines (either BRCA-wild type or mutant) were treated with PARPi after CCDC6 was attenuated by silencing or by inhibiting USP7, a CCDC6-deubiquitinating enzyme, and the effects on cell survival were assessed. At the cellular and molecular levels, the processes underlying the CCDC6-dependent modification of drugs’ sensitivity were examined. Patient-derived xenografts (PDXs) were immunostained for CCDC6, and the expression of the protein was analysed statistically after digital or visual means. Results HGSOC cells acquired PARPi sensitivity after CCDC6 depletion. Notably, CCDC6 downregulation restored the PARPi sensitivity in newly generated or spontaneously resistant cells containing either wild type- or mutant-BRCA2. When in an un-phosphorylated state, the CCDC6 residue threonine 427 is crucial for effective CCDC6-PP4 complex formation and PP4 sequestration, which maintains high γH2AX levels and effective HR. Remarkably, the PP4-dependent control of HR repair is influenced by the CCDC6 constitutively phosphorylated mutant T427D or by the CCDC6 loss, favouring PARPi sensitivity. As a result, the PP4 regulatory component PP4R3α showed to be essential for both the activity of the PP4 complex and the CCDC6 dependent PARPi sensitivity. It's interesting to note that immunohistochemistry revealed an intense CCDC6 protein staining in olaparib-resistant HGSOC cells and PDXs. Conclusions Our findings suggest that the physical loss or the functional impairment of CCDC6 enhances the PP4c complex activity, which causes BRCAness and PARPi sensitivity in HGSOC cells. Moreover, CCDC6 downregulation might overcome PARPi resistance in HGSOCs, thus supporting the potential of targeting CCDC6 by USP7 inhibitors to tackle PARPi resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Three drops of Reagent 1 were added into centre of Cytoblock cassette well and spun at 1500 rpm for 5 min. The Cytoblock cassette was processed in a standard tissue processor [ 36 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Ccdc6 Protein Levels Contribute To the Differential Sensitiv...mentioning

confidence: 99%

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The disruption of the CCDC6 – PP4 axis induces a BRCAness like phenotype and sensitivity to PARP inhibitors in high-grade serous ovarian carcinoma

Morra

Merolla

Damia

et al. 2022

J Exp Clin Cancer Res

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“…Recently, the CCDC6 has emerged as a new regulator of ferroptotic response [50]. CCDC6 has been characterized as a tumor suppressor gene based on its functions in regulating apoptosis and DNA damage response [51].…”

Section: Xct-mediated Ferroptosis Inhibition Contributes To Tumor Dev...mentioning

confidence: 99%

A xCT role in tumour-associated ferroptosis shed light on novel therapeutic options

Criscuolo

Morra

Celetti

2022

Exploration of Targeted Anti-Tumor Therapy

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Solute carrier family 7 member 11 (SLC7A11; also known as xCT), a key component of the cystine/glutamate antiporter, is essential for the maintenance of cellular redox status and the regulation of tumor-associated ferroptosis. Accumulating evidence has demonstrated that xCT overexpression, resulting from different oncogenic and tumor suppressor signaling, promotes tumor progression and multidrug resistance partially via suppressing ferroptosis. In addition, recent studies have highlighted the role of xCT in regulating the metabolic flexibility in cancer cells. In this review, the xCT activities in intracellular redox balance and in ferroptotic cell death have been summarized. Moreover, the role of xCT in promoting tumor development, drug resistance, and nutrient dependency in cancer cells has been explored. Finally, different therapeutic strategies, xCT-based, for anti-cancer treatments have been discussed.

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The amino acid transporter SLC7A11-mediated crosstalk implicated in cancer therapy and the tumor microenvironment

Chen²,

Zhang³

et al. 2022

Biochemical Pharmacology

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The tumour suppressor CCDC6 is involved in ROS tolerance and neoplastic transformation by evading ferroptosis

Cited by 4 publications

References 63 publications

The disruption of the CCDC6 – PP4 axis induces a BRCAness like phenotype and sensitivity to PARP inhibitors in high-grade serous ovarian carcinoma

The disruption of the CCDC6 – PP4 axis induces a BRCAness like phenotype and sensitivity to PARP inhibitors in high-grade serous ovarian carcinoma

A xCT role in tumour-associated ferroptosis shed light on novel therapeutic options

The amino acid transporter SLC7A11-mediated crosstalk implicated in cancer therapy and the tumor microenvironment

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