Chimeric SFT2D2‐TBX19 Promotes Prostate Cancer Progression by Encoding TBX19‐202 Protein and Stabilizing Mitochondrial ATP Synthase through ATP5F1A Phosphorylation

Specific chimeric RNAs and their products are consistently regarded as ideal tumor diagnostic markers and therapeutic targets. Chimeric RNAs can mediate tumor cell plasticity, neuroendocrine processes, polarization of tumor‐associated macrophages, and resistance to chemotherapy and immunotherapy. However, the discovery of chimeric RNAs in prostate cancer is still in its early stages. This study identifies the chimeric SFT2D2‐TBX19 as a novel transcript encoding the TBX19‐202 protein. Both TBX19‐202 and its parental TBX19, which share homologous amino acid sequences, enhance prostate cancer cell proliferation, migration, and invasion. Additionally, SFT2D2‐TBX19 also functions as a lncRNA, interacting with the ATP synthase F1 subunit ATP5F1A, thereby increasing ATP5F1A phosphorylation mediated by TNK2/ACK1, which stabilizes the interaction between ATP5F1A and ATP5F1B. The region spanning 1801‐2400 bp of SFT2D2‐TBX19 and the intermediate structural domain of ATP5F1A are crucial functional areas. This stabilization of ATP5F1A and ATP5F1B enhances mitochondrial ATP synthase activity and ATP production. Even under conditions of mitochondrial vulnerability, SFT2D2‐TBX19 protects mitochondrial structural stability to maintain prostate cancer cell proliferation. This research provides comprehensive evidence that chimeric SFT2D2‐TBX19 promotes prostate cancer progression by encoding the TBX19‐202 protein and stabilizing mitochondrial ATP synthase via ATP5F1A phosphorylation. These findings highlight SFT2D2‐TBX19 as a potential therapeutic target for prostate cancer. SFT2D2‐TBX19 functions as a lncRNA capable of interacting with the ATP synthase F1 subunit ATP5F1A, enhancing its phosphorylation via TNK2/ACK1, which in turn stabilizes the interaction between ATP5F1A and ATP5F1B. Additionally, SFT2D2‐TBX19 could also encode TBX19‐202, which shares a similar oncogenic role with the parental TBX19 in promoting the progression of prostate cancer.