Biology subjects

Criscuolo, D.

Publications and source records attributed to Criscuolo, D..

3 recordsLinked to original sources

bioRxiv2026

KRAS-Mediated CCDC6 Degradation Drives xCT Upregulation and Ferroptosis Evasion

Oncogenic KRAS mutations drive tumorigenesis by promoting pro-survival signaling and metabolic reprogramming, including the maintenance of redox balance to evade oxidative stress. A key mechanism involves the upregulation of the xCT cystine/glutamate antiporter, which sustains glutathione (GSH) synthesis and protects cells from oxidative damage and ferroptosis. While it is known that the ETS1-ATF4 complex mediates transcriptional upregulation of xCT, the upstream regulators linking KRAS signaling to this axis remain to be fully defined. Here, we demonstrate that oncogenic KRAS signaling induces the GSK3{beta}-mediated proteasomal degradation of the tumor suppressor CCDC6. We show that CCDC6 acts as a negative regulator of the xCT-promoting transcription factor ATF4 by directly interacting with it and preventing its recruitment to the xCT promoter. Consequently, KRAS-driven CCDC6 degradation disinhibits ATF4, leading to increased xCT expression, elevated intracellular GSH, and enhanced resistance to ferroptosis. Crucially, pharmacological inhibition of CCDC6 turnover using proteasome, GSK3{beta}, or specific KRAS mutant inhibitors (Sotorasib, Adagrasib, HRS4642) restored CCDC6 protein levels and robustly sensitized KRAS-mutated cells to ferroptosis-inducing agents like Sulfasalazine. Furthermore, validation in preclinical models and human colorectal cancer samples revealed that CCDC6 protein levels are predominantly downregulated in KRAS-mutant cases This work uncovers a novel KRAS/CCDC6/xCT signaling axis that mediates ferroptosis resistance in KRAS-mutated cancers. Moreover, it identifies CCDC6 turnover as a critical vulnerability and a promising therapeutic target to enhance the efficacy of ferroptosis-inducing agents.

cancer biology↗

bioRxiv2025

Using CCDC6 immunostaining in conjunction with the RAD51 HRD assay as a novel approach to expand PARPi treatment eligibility in HGSOC patients

PurposeHGSOC patients with BRCA1/2 mutations show HRD and PARPi sensitivity. Notably, HRD and PARPi response can occur without BRCA mutations, suggesting other factors are involved. Loss of CCDC6 function can lead to HRD and PARPi sensitivity in HGSOC cells, making CCDC6 a potential therapeutic target and biomarker. Three CCDC6 missense mutations in HGSOC prompted investigation into their impact on HRD. Analyzing CCDC6 expression, localization and HRD data in the MITO16A trial aims to clarify the CCDC6-HRD relationship in a large cohort. Experimental DesignThe biochemical and morphological effects of CCDC6 mutants on the native protein were examined using pull-down assays and immunofluorescence. HR-reporter and cell viability assays determined the impact of these mutants on HRD and PARPi sensitivity. CCDC6 histochemical score and intracellular-localization were assessed in MITO16A samples after immunostaining and digitalization. ResultsCCDC6-mutated isoforms act as dominant-negative, preventing native CCDC6 nuclear translocation, disrupting RAD51 foci and HR-repair, and increasing PARPi sensitivity. In the MITO16A patient sample set, 66 of 185 (35%) showed barely detectable CCDC6 or nuclear exclusion ("CCDC6-inactive"). CCDC6 impairment in these "CCDC6-inactive" samples was associated with HRD in 75% (30/40) of suitable samples analyzed by the RAD51 test and in 52% (34/65) of suitable samples analyzed by genomic HRD testing, even in the presence of wild-type BRCA1/BRCA2 genes. ConclusionThe association between CCDC6 inactivity and HRD, both at genomic and functional level, occurred even in presence of wild-type BRCA1/BRCA2 genes, suggesting that CCDC6 may play a crucial role in DNA repair pathways independent of these well-known genes.

cancer biology↗

bioRxiv2023

Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins

A complex interplay between mRNA translation and cellular respiration has been recently unveiled, but its regulation in humans is poorly characterized in either health or disease. Cancer cells radically reshape both biosynthetic and bioenergetic pathways to sustain their aberrant growth rates. In this regard, we have shown that the molecular chaperone TRAP1 not only regulates the activity of respiratory complexes, behaving alternatively as an oncogene or a tumor suppressor, but also plays a concomitant moonlighting function in mRNA translation regulation. Herein we identify the molecular mechanisms involved, demonstrating that TRAP1: i) binds both mitochondrial and cytosolic ribosomes as well as translation elongation factors, ii) slows down translation elongation rate, and iii) favors localized translation in the proximity of mitochondria. We also provide evidence that TRAP1 is coexpressed in human tissues with the mitochondrial translational machinery, which is responsible for the synthesis of respiratory complex proteins. Altogether, our results show an unprecedented level of complexity in the regulation of cancer cell metabolism, strongly suggesting the existence of a tight feedback loop between protein synthesis and energy metabolism, based on the demonstration that a single molecular chaperone plays a role in both mitochondrial and cytosolic translation, as well as in mitochondrial respiration.

biochemistry↗