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The ST6GAL1 sialyltransferase, which adds α2–6 linked sialic acids to N-glycosylated proteins, is overexpressed in a wide range of human malignancies. Recent studies have established the importance of ST6GAL1 in promoting tumor cell behaviors such as invasion, resistance to cell stress and chemoresistance. Furthermore, ST6GAL1 activity has been implicated in imparting cancer stem cell characteristics. However, despite the burgeoning interest in the role of ST6GAL1 in the phenotypic features of tumor cells, insufficient attention has been paid to the molecular mechanisms responsible for ST6GAL1 upregulation during neoplastic transformation. Evidence suggests that these mechanisms are multifactorial, encompassing genetic, epigenetic, transcriptional and posttranslational regulation. The purpose of this review is to summarize current knowledge regarding the molecular events that drive enriched ST6GAL1 expression in cancer cells.

Interest has emerged in the therapeutic potential of inhibiting store operated calcium (Ca2+) entry (SOCE) for melanoma and other cancers because malignant cells exhibit a strong dependence on Ca2+ flux for disease progression. We investigated the effects of deleting Selenoprotein K (SELENOK) in melanoma since previous work in immune cells showed SELENOK was required for efficient Ca2+ flux through the endoplasmic reticulum Ca2+ channel protein, inositol 1,4,5-trisphosphate receptor (IP3R), which is due to the role SELENOK plays in palmitoylating and stabilizing the expression of IP3R. CRISPR/Cas9 was used to generate SELENOK-deficiency in human melanoma cells and this led to reduced Ca2+ flux and impaired IP3R function, which inhibited cell proliferation, invasion, and migration. Ca2+-dependent signaling through calcineurin was inhibited with SELENOK-deficiency, and gene array analyses together with evaluation of transcript and protein levels showed altered transcriptional programs that ultimately disrupted stemness and pro-growth properties. In vivo investigations were conducted using the Grm1-Tg transgenic mouse strain that develops spontaneous metastatic melanoma, which was crossed with SELENOK-/- mice to generate the following littermates: Grm1-Tg/SELENOK-/-, Grm1-Tg/SELENOK-/+, Grm1-Tg/SELENOK+/+. SELENOK-deficiency in Grm1-Tg/SELENOK-/- male and female mice inhibited primary tumor growth on tails and ears and reduced metastasis to draining lymph nodes down to levels equivalent to non-tumor control mice. Cancer stem cell pools were also decreased in Grm1-Tg/SELENOK-/- mice compared to littermates. These results suggest that melanoma requires SELENOK expression for IP3R dependent maintenance of stemness, tumor growth and metastasic potential, thus revealing a new potential therapeutic target for treating melanoma and possibly other cancers.

Calpain‐2 levels are higher in colorectal tumors resistant to chemotherapy and previous work showed calpain‐2 inhibitor therapy reduced inflammation‐driven colorectal cancer, but direct effects of the inhibitor on colon cancer cells themselves were not demonstrated. In the present study, five human colon cancer cell lines were directly treated with a calpain‐2 inhibitor and results showed increased cell death in 4 of 5 cell lines and decreased anchorage‐independent growth for all cell five lines. When tested for levels of calpain‐2, three cell lines exhibited increasing levels of this enzyme: HCT15 (low), HCC2998 (medium), and HCT116 (significantly higher). This was consistent with gel shift assays showing that calpain‐2 inhibitor reduced of NF‐κB nuclear translocation most effectively in HCT116 cells. Ability of calpain‐2 inhibitor to impede tumor progression in vivo was evaluated using intrarectal transplant of luciferase‐expressing cells for these three cell lines. Results showed that calpain‐2 inhibitor therapy reduced tumor growth and increased survival only in mice injected with HCT116 cells. These data suggest calpain‐2 inhibitor treatment may be most effective on colorectal tumors expressing highest levels of calpain‐2.

Galectin-9 has emerged as a promising biological target for cancer immunotherapy due to its role as a regulator of macrophage and T-cell differentiation. In addition, its expression in tumor cells modulates tumor cell adhesion, metastasis, and apoptosis. Malignant mesothelioma (MM) is an aggressive neoplasm of the mesothelial cells lining the pleural and peritoneal cavities, and in this study, we found that both human MM tissues and mouse MM cells express high levels of galectin-9. Using a novel monoclonal antibody (mAb) (Clone P4D2) that binds the C-terminal carbohydrate recognition domain (CRD) of galectin-9, we demonstrate unique agonistic properties resulting in MM cell apoptosis. Furthermore, the P4D2 mAb reduced tumor-associated macrophages differentiation toward a protumor phenotype. Importantly, these effects exerted by the P4D2 mAb were observed in both human and mouse in vitro experiments and not observed with another antigalectin-9 specific mAb (clone P1D9) that engages the N-terminus CRD of galectin-9. In syngeneic murine models of MM, P4D2 mAb treatment inhibited tumor growth and improved survival, with tumors from P4D2-treated mice exhibited reduced infiltration of tumor-associated M2 macrophages. This was consistent with an increased production of inducible nitric oxide synthase, which is a major enzyme-regulating macrophage inflammatory response to cancer. These data suggest that using an antigalectin 9 mAb with agonistic properties similar to those exerted by galectin-9 may provide a novel multitargeted strategy for the treatment of mesothelioma and possibly other galectin-9 expressing tumors.

Cancer survival is largely impacted by the dissemination of cancer cells from the original tumor site to secondary tissues or organs through metastasis. Targets for anti-metastatic therapies have recently become a focus of research, but progress will require a better understanding of the molecular mechanisms driving metastasis. Selenoproteins play important roles in many of the cellular activities underlying metastasis including cell adhesion, matrix degradation and migration, invasion into the blood and extravasation into secondary tissues, and subsequent proliferation into metastatic tumors along with the angiogenesis required for growth. In this review the roles identified for different selenoproteins in these steps and how they may promote or inhibit metastatic cancers is discussed. These roles include selenoenzyme modulation of redox tone and detoxification of reactive oxygen species, calcium homeostasis and unfolded protein responses regulated by endoplasmic reticulum selenoproteins, and the multiple physiological responses influenced by other selenoproteins.

Interest has emerged in the therapeutic potential of inhibiting store operated calcium (Ca