Abstract
Signal transducer and activator of transcription (STAT)3 and STAT5 are important transcription factors that are able to mediate or even drive cancer progression through hyperactivation or gain-of-function mutations. Mutated STAT3 is mainly associated with large granular lymphocytic T-cell leukemia, whereas mutated STAT5B is associated with T-cell prolymphocytic leukemia, T-cell acute lymphoblastic leukemia and γδ T-cell-derived lymphomas. Hyperactive STAT3 and STAT5 are also implicated in various hematopoietic and solid malignancies, such as chronic and acute myeloid leukemia, melanoma or prostate cancer. Classical understanding of STAT functions is linked to their phosphorylated parallel dimer conformation, in which they induce gene transcription. However, the functions of STAT proteins are not limited to their phosphorylated dimerization form. In this review, we discuss the functions and the roles of unphosphorylated STAT3/5 in the context of chromatin remodeling, as well as the impact of STAT5 oligomerization on differential gene expression in hematopoietic neoplasms. The central involvement of STAT3/5 in cancer has made these molecules attractive targets for small-molecule drug development, but currently there are no direct STAT3/5 inhibitors of clinical grade available. We summarize the development of inhibitors against the SH2 domains of STAT3/5 and discuss their applicability as cancer therapeutics.
Highlights
The Janus kinase/Signal transducer and activator of transcription (JAK-STAT) pathway is one of the core cancer pathways that integrates signals from cytokines, hormones and growth factors to induce or repress gene expression in cells [1]
STAT1 was shown to be an oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL) and ALK+ anaplastic large cell lymphoma (ALCL), and STAT1 is associated with the JAK2 exon 12 mutation in the progression of myeloproliferative neoplasms (MPNs) [7,8,9]
STAT3 and STAT5 proteins are of particular interest in cancer research, as their hyperactivation was reported in processes ranging from inflammation and autoimmunity to infection and cancer
Summary
The Janus kinase/Signal transducer and activator of transcription (JAK-STAT) pathway is one of the core cancer pathways that integrates signals from cytokines, hormones and growth factors to induce or repress gene expression in cells [1]. STAT1−/− mice are more prone to tumor development and STAT1 deletion in leukemic cells decreases MHC class I expression [4,5]. In a v-abl-driven model of STAT1−/− leukemic cells initially harboring low MHC class I, enhanced MHC class I expression was gained during the disease progression, thereby reducing tumor recognition by NK cells [6]. STAT1 was shown to be an oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL) and ALK+ anaplastic large cell lymphoma (ALCL), and STAT1 is associated with the JAK2 exon 12 mutation in the progression of myeloproliferative neoplasms (MPNs) [7,8,9]. Associations of STAT3 and STAT5 with cancer progression are well established and heavily studied, and are the main focus of this review
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