Galectins are small unglycosylated soluble lectins distributed both inside and outside the cells. They share a conserved domain for the recognition of carbohydrates (CRD). Although galectins have a common affinity for β-galatosides, they exhibit different binding preferences for complex glycans. First described twenty years ago, galectin-7 is a prototypic galectin, with a single CRD, able to form divalent homodimers. This lectin, which is mainly expressed in stratified epithelia, has been described in epithelial tissues as being involved in apoptotic responses, in proliferation and differentiation but also in cell adhesion and migration. Most members of the galectins family have been associated with cancer biology. One of the main functions of galectins in cancer is their immunomodulating potential and anti-angiogenic activity. Indeed, galectin-1 and -3, are already targeted in clinical trials. Another relevant function of galectins in tumour progression is their ability to regulate cell migration and cell adhesion. Among these galectins, galectin-7 is abnormally expressed in various cancers, most prominently in carcinomas, and is involved in cancer progression and metastasis but its precise functions in tumour biology remain poorly understood. In this issue, we will focus on the physiological functions of galectin-7 in epithelia and present the alterations of galectin-7 expression in carcinomas with the aim to describe its possible functions in tumour progression.

Re-epithelialisation of wounded epidermis is ensured by collective cell migration of keratinocytes. Efficient collective migration requires the maintenance of intercellular adhesion, notably through adherens junctions, to favour cell communication, support tension forces and coordinated movement . Galectin-7, a soluble lectin expressed in stratified epithelia, has been previously implicated in cell migration and intercellular adhesion. Here, we revealed a new function of galectin-7 in the control of directionality and collective behaviour in migrating keratinocytes. Consistently, we identified galectin-7 as a direct partner of E-cadherin, a key component of adherens junctions. Unexpectedly, this interaction does not require glycosylation motifs. Focusing on the underlying mechanisms, we showed that galectin-7 stabilizes E-cadherin at the plasma membrane, restraining its endocytosis. Interestingly, galectin-7 silencing decreases E-cadherin-mediated intercellular adhesion. Consequently, this study not only identifies a new stabilizer of adherens junctions but also emphasises the importance of the interplay between E-cadherin turnover and intercellular adhesion strength.

SETD2 is known to be the unique histone methyltransferase responsible for the trimethylation of the lysine 36 of histone H3 thus generating H3K36me3. This epigenetic mark is critical for transcriptional activation and elongation, DNA repair, mRNA splicing, and DNA methylation. Recurrent SETD2-inactivating mutations and altered H3K36me3 levels are found in cancer at high frequency and numerous studies indicate that SETD2 acts as a tumor suppressor. Recently, SETD2 was further shown to methylate non-histone proteins particularly the cytoskeletal proteins tubulin and actin with subsequent impacts on cytoskeleton structure, mitosis and cell migration. Herein, we provide a review of the role of SETD2 in different cancers with special emphasis on the structural basis of the functions of this key lysine methyltransferase. Moreover, beyond the role of this enzyme in epigenetics and H3K36me3-dependent processes, we highlight the putative role of "non-epigenetic/H3K36me3" functions of SETD2 in cancer, particularly those involving the cytoskeleton.

Maintaining epithelial homeostasis is crucial to allow embryo development but also the protective barrier which is ensured by the epidermis. This homeostasis is regulated through the expression of several molecules among which EGFR and E-cadherin which are of major importance. Indeed, defects in the regulation of these proteins lead to abnormalities in cell adhesion, proliferation, differentiation, and migration. Hence, regulation of these two proteins is of the utmost importance as they are involved in numerous skin pathologies and cancers. In the last decades it has been described several pathways of regulation of these two proteins and notably several mechanisms of cross-regulation between these partners. In this review, we aimed to describe the current understanding of the regulation of EGFR and interactions between EGFR and E-cadherin and, in particular, the implication of these cross-regulations in epithelium homeostasis. We pay particular attention to PTP1B, a phosphatase involved in the regulation of EGFR.

Human protein tyrosine phosphatase 1B (PTP1B) is a ubiquitous non-receptor tyrosine phosphatase that serves as a major negative regulator of tyrosine phosphorylation cascades of metabolic and oncogenic importance such as the insulin, epidermal growth factor receptor (EGFR), and JAK/STAT pathways. Increasing evidence point to a key role of PTP1B-dependent signaling in cancer. Interestingly, genetic defects in PTP1B have been found in different human malignancies. Notably, recurrent somatic mutations and splice variants of PTP1B were identified in human B cell and Hodgkin lymphomas. In this work, we analyzed the molecular and functional levels of three PTP1B mutations identified in primary mediastinal B cell lymphoma (PMBCL) patients and located in the WPD-loop (V184D), P-loop (R221G), and Q-loop (G259V). Using biochemical, enzymatic, and molecular dynamics approaches, we show that these mutations lead to PTP1B mutants with extremely low intrinsic tyrosine phosphatase activity that display alterations in overall protein stability and in the flexibility of the active site loops of the enzyme. This is in agreement with the key role of the active site loop regions, which are preorganized to interact with the substrate and to enable catalysis. Our study provides molecular and enzymatic evidence for the loss of protein tyrosine phosphatase activity of PTP1B active-site loop mutants identified in human lymphoma.

E-cadherin and EGFR are known to be closely associated hence regulating differentiation and proliferation notably in epithelia. We have previously shown that galectin-7 binds to E-cadherin and favors its retention at the plasma membrane. In this study, we shed in light that galectin-7 establishes a physical link between E-cadherin and EGFR. Indeed, our results demonstrate that galectin-7 also binds to EGFR, but unlike the binding to E-cadherin this binding is sugar dependent. The establishment of E-cadherin/EGFR complex and the binding of galectin-7 to EGFR thus lead to a regulation of its signaling and intracellular trafficking allowing cell proliferation and migration control. In vivo observations further support these results since an epidermal thickening is observed in galectin-7 deficient mice. This study therefore reveals that galectin-7 controls epidermal homeostasis through the regulation of E-cadherin/EGFR balance.