Bone Metastatic Progression of Prostate Cancer is Regulated by TRIM28-LDHA Mediated Metabolism

Castration-resistant prostate Cancer (CRPC), an advanced stage of prostate Cancer (PCa), often leads to fatal bone metastasis. The vast majority of PCa patients who present with bone metastases suffer from bone lesions and Other complications. Androgen Receptor (AR) inhibitors, while improved, lack curative efficacy, necessitating an urgent demand for the development of innovative therapeutic strategies. TRIM28, also known as KAP1, is a transcription factor regulated by site-specific phosphorylation. Our recent study demonstrated that RSK1 is the protein kinase that directly phosphorylates TRIM28 at S473; as such, pS473-TRIM28 promotes the transcriptional activation of its gene targets. In this study, we reveal that TRIM28 S473 phosphorylation is readily detected in CRPC bone metastases, which is consistent with the previous report that RSK kinase is activated in PCa bone metastases. Using bioinformatic and genomic analysis, we uncovered that Lactate Dehydrogenase A (LDHA) is a novel TRIM28-induced gene in bone metastatic PCa. TRIM28 promotes the transcriptional activation of LDHA in a pS473-TRIM28 dependent manner. As such, TRIM28 is involved in LDH-related activities including lactate production and glycolysis. We also demonstrate that the TRIM28-LDHA axis is required for prostate tumor progression using an orthotopic bone injection model. Lastly, the application of an LDH inhibitor mitigates PCa development in bone. In summary, our study reveals an important role of the TRIM28-LDHA axis in PCa progression in bone, which may be targeted to mitigate the disease in the metastasis stage. Implications: TRIM28 upregulates LDHA and glycolysis, propelling prostate tumors in bone; pharmacologic LDH blockade mitigates disease.