The zinc finger protein Snail is a master regulator of epithelial-mesenchymal transition (EMT) and a strong inducer of tumor metastasis, yet the signal cascades triggered by Snail have not been completely revealed. Here, we report the discovery of the sulfation program that can be induced by Snail in breast cancer cells, and which plays an essential role in cell migration and metastasis. Specifically, Snail induces the expression of PAPSS2, a gene that encodes a rate-limiting enzyme in sulfation pathway, and VCAN, a gene that encodes the chondroitin sulfate proteoglycan Versican in multiple breast cancer cells. Depletion of PAPSS2 in MCF7 and MDA-MB-231 cells results in reduced cell migration, while overexpression of PAPSS2 promotes cell migration. Moreover, MDA-MB-231-shPAPSS2 cells display a significantly lower rate of lung metastasis and lower number of micrometastatic nodules in nude mice, and conversely, MDA-MB-231-PAPSS2 cells increase lung metastasis. Similarly, depletion of VCAN dampens the cell migration activity induced by Snail or PAPSS2 in MCF 10A cells. Moreover, PAPSS inhibitor sodium chlorate effectively decreases cell migration induced by Snail and PAPSS2. More importantly, the expression of Snail, PAPSS2, and VCAN is positively correlated in breast cancer tissues. Together, these findings are important for understanding the genetic programs that control tumor metastasis and may identify previously undetected therapeutic targets to treat metastatic disease.

The LIM protein AJUBA is a scaffold protein participating in the regulation of cell adhesion, mitosis, DNA damage, cell differentiation, proliferation, migration and gene transcription. However, its roles in tumorigenesis and progression are poorly defined. Here, we report that AJUBA is highly expressed in colorectal cancer (CRC) and promotes CRC cell growth in culture and in xenografted mice via an inhibition of apoptosis. AJUBA represses the expression of IFIT2 gene, an interferon-stimulated gene and a known apoptosis inducer and tumour suppressor to mediate its resistance to apoptosis. Mechanistic investigations reveal that AJUBA specifically binds the FERM domain of JAK1 to dissociate JAK1 from the IFNγ recepter, resulting in an inhibition of STAT1 phosporylation and concomitantly its nuclear translocation. Clinically, the level of AJUBA in CRC specimens is negatively correlated with the levels of IFIT2 and pSTAT1. Collectively, these studies demonstrate that AJUBA can promote CRC growth via inhibiting apoptosis and serve as a target for the therapeutics and a marker for diagnosis of CRC.

Transcriptional repressor Snail is a master regulator of epithelial–mesenchymal transition (EMT), yet the epigenetic mechanism governing Snail to induce EMT is not well understood. Here, we report that in pancreatic ductal adenocarcinoma (PDAC), elevated levels of the ubiquitin E3 ligase Ring1B and Snail, along with elevated monoubiquitination of H2A at K119 (H2AK119Ub1), are highly correlated with poor survival. Mechanistic investigations identified Ring1B as a Snail-interacting protein and showed that the carboxyl zinc fingers of Snail recruit Ring1B and its paralog Ring1A to repress its target promoters. Simultaneous depletion of Ring1A and Ring1B in pancreatic cancer cells decreased Snail binding to the target chromatin, abolished H2AK119Ub1 modification, and thereby compromised Snail-mediated transcriptional repression and cell migration. We found that Ring1B and the SNAG-associated chromatin modifier EZH2 formed distinct protein complexes with Snail and that EZH2 was required for Snail-Ring1A/B recruitment to the target promoter. Collectively, our results unravel an epigenetic mechanism underlying transcriptional repression by Snail, suggest Ring1A/B as a candidate therapeutic target, and identify H2AK119Ub1 as a potential biomarker for PDAC diagnosis and prognosis. Cancer Res; 74(16); 4353-63. ©2014 AACR

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