SMC4 promotes prostate cancer organ-specific metastasis by modifying cancer cells metabolic

Structural maintenance of chromosomes 4 (SMC4), one subunit of condensin complexes, is a key structural component of mitotic chromosomes. Accumulating evidence has suggested that SMC4 regulates prostate carcinogenesis. However, its roles on regulation of prostate cancer development remain unclear. Our previous studies showed that the expression of SMC4 is increased in highly lung-metastatic prostate cancer cells, RM1-LM, an organ-specific metastasis cell line that we developed. To investigate the function of SMC4, SMC4 gene was knockdown in RM1-LM cells by CRISPR/Cas9 system. Knockdown of SMC4 significantly diminished the cancer cell growth in RM1-LM. In addition, transwell assay results showed that SMC4 knockdown in RM1-LM suppressed the cell migration and invasion. Furthermore, we observed that SMC4 protein is important in the non-dividing phase of the cell cycle. In particular, cell cycle flow cytometry analysis indicated that SMC4 knockdown leaded to cell arrest in S phase. Finally, RM1-LM cells showed increased lung metastases compared with RM1-SMC4+/- cells in a murine model. The H&E and IHC results confirmed that RM1-LM cells induced greater number of lung metastases and colonization than RM1-SMC4+/-cells, suggesting the loss of SMC4 suppressed prostate cancer metastasis. The interactome of SMC4 was uncovered through IP-MS and revealed that SMC4 may interacted with GLUT1, a key protein in glycolysis pathway. The ATP rate assay and Glycolysis rate assay illustrated a significantly metabolic switch existing in RM1-SMC4+/-cells compared with their parental cells. Collectively, our study suggested that the interaction between SMC4 and GLUT1, confirmed by Co-IP, promotes prostate cancer cells metastasis via modifying the cell metabolism.