Oncogenic Activity of SLC45A2‐AMACR

Significant number of human cancers contains gene fusion between solute carrier family 45, member 2 (SLC45A2) and α‐methylacyl‐CoA racemase (AMACR). SLC45A2 is a transporter protein known to be overexpressed in melanoma, while AMACR is an enzyme involved in metabolism of branch fatty acid, and is known for its overexpression in several human malignancies. SLC45A2‐AMACR replaces 8 transmembrane and cytosolic domains of SLC45A2 with an intact racemase domain from AMACR. At least eight types of primary human malignancies and cell lines are positive for SLC45A2‐AMACR fusion. Our analysis showed that SLC45A2‐AMACR interacts and activates MAPK kinase pathway, and promote cell growth and cancer invasion both in vitro and in vivo. Hydrodynamic tail vein injection of “sleeping beauty” SLC45A2‐AMACR in conjunction with somatic Pten knockout produced spontaneous liver cancer in 4 months. Disruption of SLC45A2‐AMACR fusion in HUH7 and H1299 cells abrogated the transformation activity of these cancer cell lines, while over‐expression of the fusion gene in H1299 cells induced higher growth rate, mitgration and resistant to serum starvation induced cell death in vitro. As a result, we conclude that SLC45A2‐AMACR is a critical driver for human cancers.