SIRT6 Loss Promotes PDAC Progression by Epigenetic Induction of LIN28B

Genomic alterations in epigenetic modifier genes have been described in some pancreatic ductal adenocarcinomas (PDAC), but the mechanisms by which these alterations drive tumorigenesis are not well understood. Approximately 60% of pancreatic cancer cell lines exhibit copy-number loss of the histone deacetylase gene sirtuin 6 (SIRT6), and SIRT6 downregulation has been observed in human PDAC, prompting Kugel and colleagues to explore the role of SIRT6 in PDAC. Tissue microarrays of 120 PDAC samples confirmed that SIRT6 expression was reduced in approximately 30-40% of tumors, and low expression of SIRT6 was associated with an especially poor prognosis. Moreover, in a Kras-mutant mouse model of PDAC, Sirt6 knockdown accelerated the development of lethal pancreas tumors and enhanced lung metastasis, further establishing SIRT6 as a PDAC tumor suppressor. SIRT6 loss increased acetylation of histone H3 K56 (H3K56Ac) and H3K9Ac and increased chromatin-bound MYC, thereby promoting cellular proliferation. Chromatin immunoprecipitation sequencing (ChIP-seq) to identify loci differentially marked by H3K56Ac following SIRT6 knockout identified the oncofetal RNA-binding protein LIN28B that is normally silenced in differentiated cells, suggesting it may be activated by loss of SIRT6 histone deacetylase activity in PDAC. Indeed, expression of SIRT6 and LIN28B were inversely correlated in PDAC cell lines, and LIN28B was upregulated and required for the growth and survival of PDAC cells with SIRT6 depletion. SIRT6 repressed MYC-dependent transcription of LIN28B via H3K56 and H3K9 deacetylation at the LIN28 promoter, which subsequently relieved LIN28-mediated suppression of let-7 miRNA biogenesis and reduced expression of genes normally silenced by let-7 that have been implicated in tumor progression. Consistent with these findings, elevated LIN28B expression was associated with a poor prognosis in patients with PDAC and an increased expression of MYC and let-7 targets. Overall, these findings indicate that LIN28B is a critical PDAC oncogene, and suggest that targeting components of the LIN28B/let-7 pathway may be beneficial in SIRT6-deficient PDAC.

Kugel S, Sebastián C, Fitamant J, Ross KN, Saha SK, Jain E, et al. SIRT6 suppresses pancreatic cancer through control of Lin28b. Cell 2016 May 12 [Epub ahead of print].