Biology subjects

Kukkula, A.

Publications and source records attributed to Kukkula, A..

2 recordsLinked to original sources

bioRxiv2026

SUMOylation is a Therapeutic Vulnerability in High-risk Neuroblastoma

Neuroblastoma (NB) is one of the most common solid malignancies in children, and high-risk patients have poor prognosis, underscoring the need for novel therapeutic agents. The small ubiquitin-like modifier (SUMO) is a reversible post-translational modification that regulates various protein functions, and the first-in-class SUMOylation inhibitor TAK-981 (subasumstat) is currently in clinical trials in adult cancer patients. However, the role of SUMOylation in NB pathogenesis remains poorly characterized. We show that SUMOylation-catalyzing enzymes, SAE1, SAE2, and UBE2I, are highly expressed in malignant neuroendocrine cells, and their expression correlate with poor survival in NB patients and associate with advanced stage, MYCN amplifications, and downregulation of late differentiation markers. The peripheral nervous system lineage and NB cell lines are highly sensitive to the CRISPR knockout of SAE1 and SAE2, suggesting SUMOylation as promising therapeutic target in NB. Accordingly, TAK-981-mediated inhibition of SUMOylation reduces growth of NB cells in both in vitro and in vivo models through induction of apoptosis and perturbation of differentiation-associated pathways. Sensitivity to SUMOylation inhibition is greatest in NB cells with low expression of favorable late neuroblast markers and is independent of MYCN amplification status. Moreover, TAK-981 is effective in combination with differentiation-inducing all-trans retinoic acid and the DNA methyltransferase inhibitor decitabine. Mechanistically, combination of TAK-981 and retinoic acid potently downregulates retinoic acid receptor alpha (RAR) expression, whereas inhibition of SUMOylation combined with decitabine induces a strong accumulation of DNA damage. Taken together, these findings establish SUMO pathway components as potential prognostic markers and SUMOylation as a therapeutic vulnerability in high-risk NB.

cancer biology↗

bioRxiv2024

Functionality of BRCA1 supports the survival of prostate cancer cells during the development of castration resistance

Androgen deprivation therapy (ADT; castration) is the main treatment option for metastatic prostate cancer (PCa), but eventually, castration-resistant prostate cancer (CRPC) develops with no curative treatments. In CRPC, more than 20% of men carry mutations in DNA damage response (DDR) genes, including BRCA1/2. In this study, we elucidated the prostate tissue-specific functional role of BRCA1 protein. Our results indicate that DDR is dynamically regulated by androgen receptor (AR) signaling, and AR activation by the natural ligand dihydrotestosterone strongly downregulates the expression of BRCA1 in multiple cell lines. Consistent with these findings, our analyses of patient samples and mouse xenografts showed that DNA damage and BRCA1 expression were sustained after ADT. With unbiased mass spectrometry and bioinformatics approaches as well as experimentally, we found that BRCA1 interacts with Raptor, an mTORC1 component, and regulates the mTOR signaling pathway and PCa growth in vitro. Furthermore, we found that mTOR inhibition reduced the recruitment of DDR proteins, BRCA1 and Rad51, to DNA damage sites, creating a vulnerability towards DNA damage-inducing androgen deprivation. Moreover, we observed that BRCA1 supported ADT-induced activation of the oxidative stress sensor NRF2. Our findings shed further light on the complex DDR-AR interplay in PCa and suggest that, during PCa progression, BRCA1 expression may be retained due to the beneficial modulation of mTORC1 signaling in the AR environment by BRCA1. SignificanceAndrogen receptor activation acts as a strong suppressor of BRCA1. Consequently, androgen deprivation activates BRCA1, which in turn promotes survival in castration resistance by supporting mTOR signaling and NRF2-mediated antioxidant processes.

cancer biology↗