STAT1

Official Full Name

signal transducer and activator of transcription 1

Organism

Homo sapiens

GeneID

6772

Background

The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. The protein encoded by this gene can be activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6. This protein mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli and pathogens. The protein plays an important role in immune responses to viral, fungal and mycobacterial pathogens. Mutations in this gene are associated with Immunodeficiency 31B, 31A, and 31C. [provided by RefSeq, Jun 2020]

Synonyms

CANDF7; IMD31A; IMD31B; IMD31C; ISGF-3; STAT91;

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Detailed Information

DNA-binding transcription factor Signal Transducer and Activator of Transcription 1 (STAT1) encodes two isoforms of STAT1, a and b. STAT1a is a transcriptional activator playing an important role in signaling responses to a wide variety of cytokine and growth factors, whereas STAT1b functions as a dominant negative inhibitor. Cytoplasmic Stat1 is activated by tyrosine phosphorylation, typically by members of the JAK kinase family, which leads to its translocation to the nucleus and subsequent binding to target DNA sequences. STAT1 performs multiple important biological functions in normal cells, such as cell growth inhibition, cell death promotion, cell differentiation regulation, and immune system stimulation.

Tumour suppressive functions of STAT1

Results generated from most STAT1 studies support the concept of STAT1 as a tumor suppressor. Based on the canonical role in IFNγ signaling and on studies using STAT1^-/- tumor cells and mouse models, STAT1 has been classically defined as a Th1 proimmune and antitumor transcription factor. STAT1 has also been described to regulate DNA repair pathways and to be upregulated in many late-stage human cancers, including those of the glioblastoma, colon, breast, and soft tissue sarcoma. Overexpression of the IFN-STAT1 pathway is also associated with poor prognosis of different types of cancer. Especially in breast cancers, the increased IFN-STAT1 pathway activity is considered a marker to predict chemotherapy and radiotherapy resistance.

In terms of mechanism, tumour suppression by STAT1 occurs at multiple levels: tumour cell-intrinsic growth control and cross-talk with other cells to regulate cancer immunoediting and suppress angiogenesis. STAT1 regulates cell death through transcription-dependent and transcription-independent mechanisms. As a transcription factor, STAT1 directly regulates the expression of many genes, such as BCL2 and caspases, as well as interacting with other proteins, such as TRADD and p53. Similar mechanisms by which STAT1 promotes cell death are also detected in multiple cancer cell types. Furthermore, STAT1 is considered to be a negative regulator of tumor angiogenesis in many types of cancer. For example, in non-small cell lung cancer cells, IL-27 induces mesenchymal to epithelial transition and inhibits the production of pro-angiogenic factors, such as β-catenin/N-cadherin, vimentin, E-cadherin, VEGF, CXCL5, and IL-8/CXCL8, in a STAT1-dominant pathway.

STAT1 Figure 1. Tumour suppressive functions of STAT1. (Meissl K, et al. 2017)

Tumour promoting functions of STAT1

However, the role of STAT1 as a tumor suppressor remains controversial. Aberrant STAT1 activation has been detected in some types of human cancer, such as pleural mesothelioma, head and neck cancer, breast cancer, and lymphoma. The silencing of STAT1 can enhance cell apoptosis induced by chemotherapeutic agents and radiation in renal cell carcinoma and breast cancer. Some studies reported contradictory observations indicating that patients with high expression of STAT1 and/or p-STAT1 in cancer tissues experience worse clinical outcomes in comparison to patients with low levels of STAT1 and/or p-STAT1, such as sarcoma, breast cancer and Wilms’ tumor. Other studies showed that a high p-STAT1 expression or STAT1 mRNA level is associated with poor overall survival and an advanced clinical stage in breast cancer and glioblastoma multiforme patients. In vivo studies further supported the role of STAT1 in promoting carcinogenesis.

The role of STAT1 in tumourigenesis is complex, since its functions are not restricted to tumour cells, but extend to different compartments of the tumour microenvironment. A more detailed mechanistic analysis of the tumour cell-intrinsic and extrinsic functions of STAT1 and their contribution to carcinogenesis will help to fully exploit the diagnostic and therapeutic potential of STAT1. The association of high STAT1 expression and/or activity with therapy resistant tumour types indicates that selective STAT1 inhibitors may be useful in cancer therapy. Selective inhibitors for STAT3 and STAT5 are rapidly advancing and STAT1 inhibitors are within reach. Inhibitors will help clarify the multifaceted functions of STAT1 in tumourigenesis and may open future paths in cancer therapy.

References:

Kharma B, et al. STAT1 drives tumor progression in serous papillary endometrial cancer. Cancer research, 2014, 74(22): 6519-6530.
Sharfe N, et al. Fatal combined immunodeficiency associated with heterozygous mutation in STAT1. Journal of Allergy and Clinical Immunology, 2014, 133(3): 807-817.
Meissl K, et al. The good and the bad faces of STAT1 in solid tumours. Cytokine, 2017, 89: 12-20.
Zhang Y, Liu Z. STAT1 in cancer: friend or foe?. Discovery medicine, 2017, 24(130): 19-29.

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