Dysregulated RNA Splicing targets Cancer by Proteotoxic Stress.
Cristian Prieto
IBCII - Univ. Frankfurt
Dysregulated RNA splicing and proteostatic stress are common features of many cancers, including hepatocellular carcinoma and lung adenocarcinoma. Aggressive malignancies, particularly those driven by c-MYC amplification, are highly sensitive to splicing impairment, but the molecular mechanisms remain poorly understood. Here, we show that cancer cells rely on oncogenic ubiquitin-specific peptidase 39 (USP39)-driven splicing reprogramming, induced by lactate, to balance proteostasis and support rapid proliferation. Disabling the splicing factor USP39 disrupts cancer protein homeostasis by causing the accumulation of toxic misfolded proteins from mis-spliced RNA transcripts. This proteostatic imbalance abrogates oncogenic transformation and triggers tumor regression by impairing proliferation and inducing cancer cell death. Notably, while malignant cells are highly vulnerable to this stress due to their reliance on precise splicing factors for proteostasis, non-cancerous cells largely tolerate splicing dysregulation with minimal proteotoxicity. These findings provide a compelling rationale for therapies that exploit the synthetic lethality between tumors and splicing inhibition, offering a promising strategy to target proteostatic vulnerabilities of aggressive cancers, such as c-MYC-driven tumors.
Highlights:
- Aggressive tumors upregulate lactate-driven USP39 splicing reprogramming to sustain oncogenic proliferation.
- Proteotoxicity caused by dysregulated RNA splicing disrupts MYC-driven liver malignant transformation.
- Enhanced cryptic splicing-related proteotoxic stress selectively induces cancer cell death and promotes tumor regression.
- Non-transformed cells tolerate splicing imbalance with minimal proteotoxic accumulation, highlighting cancer cell-specific vulnerabilities.