TGFβ induces a SMAD4-dependent EMT in the pancreas that promotes apoptosis.
Major finding: TGFβ induces a SMAD4-dependent EMT in the pancreas that promotes apoptosis.
Mechanism: EMT-dependent KLF5 inhibition by SNAIL switches SOX4 into a proapoptotic factor.
Impact: In certain contexts, TGFβ-induced EMT can be tumor suppressive instead of oncogenic.
Depending on the cellular context, transforming growth factor β (TGFβ) has been observed to exert protumorigenic functions, such as inducing an epithelial–mesenchymal transition (EMT), or inhibit tumorigenesis by activating apoptosis. The proapoptotic functions of TGFβ have been linked with the transcription factor SMAD4, which acts downstream of TGFβ and is frequently deleted in pancreatic ductal carcinoma (PDAC). To elucidate the mechanism by which TGFβ promotes apoptosis, David and colleagues used a Kras-mutant/Smad4-deleted PDAC murine model and found that reintroduction of SMAD4 sensitized cells to TGFβ treatment and promoted changes in cell morphology and loss of E-cadherin consistent with EMT. Moreover, SNAIL was shown to be upregulated following TGFβ treatment, and genetic depletion of SNAIL inhibited TGFβ-induced EMT, apoptosis, and accelerated pancreatic carcinogenesis in SMAD4–wild-type cells, raising the unexpected possibility that EMT precedes apoptosis and is required for TGFβ-mediated tumor suppression in the pancreas. An RNAi screen of TGFβ-responsive genes to identify those necessary for Smad4-mutant PDAC growth identified the transcription factor gene Sox4, and chromatin immunoprecipitation sequencing and motif analysis revealed that SOX4-occupied loci were enriched for binding sites of the lineage-specific transcription factor KLF5. KLF5 co-occupied the vast majority of SOX4 binding sites and suppressed TGFβ-induced apoptosis in Smad4-mutant PDAC cells, suggesting that KLF5 may determine SOX4 function in this context. Indeed, upon TGFβ-driven EMT, KLF5 expression was suppressed by EMT-associated transcription factors including SNAIL, which served as a molecular trigger to switch SOX4 function from protumorigenic to proapoptotic and led to SOX4-dependent transcription of the proapoptotic genes Bim and Bmf. Together, these data suggest that TGFβ-mediated EMT induces transcriptional reprogramming that alters the cellular KLF5:SOX4 ratio and allows for SOX4-mediated induction of apoptosis. These findings also provide an explanation for the frequent inactivation of SMAD4, but not TGFβ receptors, in pancreatic cancer, and elucidate a mechanism by which TGFβ-induced EMT is tumor suppressive in certain contexts.
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