Role of the JAK‐STAT Signalling Pathway in Cancer

The JAK-STAT pathway is important in cytokine-mediated immune responses. Research in the JAK/STAT field has elucidated its roles in various cellular processes such as proliferation, apoptosis and migration, and has found frequent dysregulation of the JAK/STAT pathway in diverse types of cancer. In recent years, JAK and STAT have also been implicated in a noncanonical mode of action: the regulation of genomic stability independent of their functions in cytokine signalling. Research in Drosophila has shown that nuclear, unphosphorylated STAT physically interacts with heterochromatin protein 1 (HP1) and stabilises its binding to heterochromatin. A similar interaction occurs in human cells, where unphosphorylated STAT5A interacts with HP1α and acts as a tumour suppressor. Nuclear JAK2, however, functions as a histone tyrosine kinase, displacing HP1α from chromatin. These data have important implications for human cancer: They suggest new drug therapies, which could target the noncanonical functions of JAK and STAT. In this article, we discuss how the canonical arm of the JAK-STAT pathway functions in tumourigenesis, focussing on JAK and on STAT1, STAT3 and STAT5. We then discuss recent findings regarding epigenetic silencing of JAK/STAT pathway components, and the direct involvement of JAK and STAT in regulating heterochromatin integrity. Key Concepts: The tyrosine kinase JAK and its downstream target STAT respond to cytokine signalling in cells. In response to cytokines, JAK itself is phosphorylated, leading to its activation. The activated JAK kinase then phosphorylates specific STATs. STAT proteins dimerise and translocate into the nucleus upon phosphorylation by JAK, where they bind to DNA and regulate transcription. Overactivation of the JAK-STAT pathway can cause cancer by bypassing apoptosis and cell cycle checkpoints. Unphosphorylated STAT is also found in the nuclei and mitochondria of cells that are not stimulated by cytokines. Mitochondrial STAT upregulates cellular respiration and can promote oncogenic transformation. Unphosphorylated nuclear STAT binds to HP1α and stabilises heterochromatin. STAT5A in colon cancer cells acts as a tumour suppressor via this mechanism. Nuclear JAK2 is a histone tyrosine kinase. Phosphorylation of histone 3 tyrosine 41 displaces HP1α/CBX5 from chromatin and contributes to tumourigenicity. In some cancers, DNA methylation suppresses the expression of inhibitory SOCS proteins, resulting in uncontrolled JAK/STAT pathway activation. Keywords: JAK; STAT; cancer; epigenetic; heterochromatin; metastasis; angiogenesis; HP1; CpG methylation