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

Castration-resistant prostate cancer, an advanced stage of prostate cancer, often leads to fatal bone metastasis. The vast majority of patients with prostate cancer who present with bone metastases suffer from bone lesions and other complications. Androgen receptor inhibitors, although improved, lack curative efficacy, necessitating an urgent demand for the development of innovative therapeutic strategies. TRIM28, also known as Krüppel-associated box-associated protein 1, is a transcription factor regulated by site-specific phosphorylation. Our recent study demonstrated that p90 ribosomal S6 kinase 1 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 castration-resistant prostate cancer bone metastases, which is consistent with the previous report that p90 ribosomal S6 kinase is activated in prostate cancer bone metastases. Using bioinformatic and genomic analyses, we uncovered that lactate dehydrogenase A (LDHA) is a novel TRIM28-induced gene in bone metastatic prostate cancer. 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 prostate cancer development in the bone. In summary, our study reveals an important role of the TRIM28-LDHA axis in prostate cancer progression in the bone, which may be targeted to mitigate the disease in the metastasis stage.

TRIM28 upregulates LDHA and glycolysis, propelling prostate tumors in the bone; pharmacologic LDH blockade mitigates disease.