Sirtuin 5‐mediated deacetylation of TAZ at K54 promotes melanoma development and lung metastasis

Abstract Nuclear accumulation of YAP/TAZ promotes tumorigenesis in several cancers, including melanoma. Although the underlying mechanisms for the nuclear retention of YAP are known, those responsible for the retention of TAZ remain unclear. We aimed to evaluate the role of a novel acetylation/deacetylation switch of TAZ that regulates its subcellular localization in lung metastasis of melanoma cells. CREB binding protein (CBP) mediated TAZ acetylation at K54 in response to stimulation with epidermal growth factor or transforming growth factor beta whereas sirtuin 5 (SIRT5) mediated its deacetylation. The acetylation of TAZ was tightly coupled with phosphorylation which, in turn, regulated its binding with the LATS2 kinase or TEAD transcription factor. We used antibodies against the K54 acetylation site and found that acetylation of TAZ promoted S89 phosphorylation via its enhanced interaction with LAST2 to promote cytosolic retention. However, SIRT5-mediated deacetylation enhanced the TAZ–TEAD interaction and promoted nuclear retention. Chromatin immunoprecipitation revealed that SIRT5-mediated deacetylation of TAZ promoted its recruitment to the connective tissue growth factor (CTGF) promoter, resulting in increased transcriptional activity. In a syngeneic mouse model, deacetylation of TAZ increased CTGF expression, promoting metastasis of melanoma cells into the lung tissue after injection of B16F10 melanocytes via tail vein. Our study revealed a novel mechanism of TAZ nuclear retention regulated by SIRT5-mediated K54 deacetylation and demonstrated the significance of TAZ deacetylation in CTGF expression and lung metastasis of melanoma cells. Our study highlights the potential implications of the SIRT5/TAZ axis for metastatic melanoma treatment.