SMYD2-dependent HSP90 methylation promotes cancer cell proliferation by regulating the chaperone complex formation.

Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that facilitates the maturation of a wide range of proteins, and it has been recognized as a crucial facilitator of oncogene addiction and cancer cell survival. Although HSP90 function is regulated by a variety of post-translational modifications, the physiological significance of methylation has not fully been elucidated. Here we demonstrate that HSP90AB1 is methylated by the histone methyltransferase SMYD2 and that it plays a critical role in human carcinogenesis. HSP90AB1 and SMYD2 can interact through the C-terminal region of HSP90AB1 and the SET domain of SMYD2. Both in vitro and in vivo methyltransferase assays revealed that SMYD2 could methylate HSP90AB1 and mass spectrometry analysis indicated lysines 531 and 574 of HSP90AB1 to be methylated. These methylation sites were shown to be important for the dimerization and chaperone complex formation of HSP90AB1. Furthermore, methylated HSP90AB1 accelerated the proliferation of cancer cells. Our study reveals a novel mechanism for human carcinogenesis via methylation of HSP90AB1 by SMYD2, and additional functional studies may assist in developing novel strategies for cancer therapy.