Dataset Information

FOXA1 overexpression suppresses interferon signaling and immune response in cancer.

ABSTRACT: Androgen receptor-positive prostate cancer (PCa) and estrogen receptor-positive luminal breast cancer (BCa) are generally less responsive to immunotherapy compared with certain tumor types such as melanoma. However, the underlying mechanisms are not fully elucidated. In this study, we found that FOXA1 overexpression inversely correlated with interferon (IFN) signature and antigen presentation gene expression in PCa and BCa patients. FOXA1 bound the STAT2 DNA-binding domain and suppressed STAT2 DNA-binding activity, IFN signaling gene expression, and cancer immune response independently of the transactivation activity of FOXA1 and its mutations detected in PCa and BCa. Increased FOXA1 expression promoted cancer immuno- and chemotherapy resistance in mice and PCa and BCa patients. These findings were also validated in bladder cancer expressing high levels of FOXA1. FOXA1 overexpression could be a prognostic factor to predict therapy resistance and a viable target to sensitize luminal PCa, BCa, and bladder cancer to immuno- and chemotherapy.

SUBMITTER: He Y

PROVIDER: S-EPMC8279591 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

FOXA1 overexpression suppresses interferon signaling and immune response in cancer.

He Yundong Y Wang Liguo L Wei Ting T Xiao Yu-Tian YT Sheng Haoyue H Su Hengchuan H Hollern Daniel P DP Zhang Xiaoling X Ma Jian J Wen Simeng S Xie Hongyan H Yan Yuqian Y Pan Yunqian Y Hou Xiaonan X Tang Xiaojia X Suman Vera J VJ Carter Jodi M JM Weinshilboum Richard R Wang Liewei L Kalari Krishna R KR Weroha Saravut J SJ Bryce Alan H AH Boughey Judy C JC Dong Haidong H Perou Charles M CM Ye Dingwei D Goetz Matthew P MP Ren Shancheng S Huang Haojie H

The Journal of clinical investigation 20210701 14

Androgen receptor-positive prostate cancer (PCa) and estrogen receptor-positive luminal breast cancer (BCa) are generally less responsive to immunotherapy compared with certain tumor types such as melanoma. However, the underlying mechanisms are not fully elucidated. In this study, we found that FOXA1 overexpression inversely correlated with interferon (IFN) signature and antigen presentation gene expression in PCa and BCa patients. FOXA1 bound the STAT2 DNA-binding domain and suppressed STAT2 D ...[more]

PMID: 34101624

Similar Datasets

Project description:Age is a major risk factor for liver cancer, as is the case for most adult human cancers. However, the underlying mechanisms are not well defined. A better understanding of the role of aging in liver and other cancers can facilitate approaches for risk assessment, early detection and prevention. We hypothesize that age-driven changes render aged liver more sensitive to oncogenic stress and hence tumorigenesis. To investigate how the liver changes with age, we documented the immune profile, transcriptome and epigenome of healthy livers from both young and aged mice, revealing pronounced alterations with aging. Notably, in aged hepatocytes, we identified heightened interferon (IFN) signaling, as well as simultaneous tumor suppressor and oncogene signaling at both bulk and single cell level, suggestive of an aged liver that is poised for neoplasia. To challenge this seemingly poised state, we employed adeno-associated virus (AAV)-mediated expression of a c-Myc oncogene in young and aged mouse liver hepatocytes in vivo. Analysis of aged hepatocytes expressing c-Myc revealed further elevated expression of IFN Stimulated Genes (ISGs). This ISG upregulation was evident in multiple models of oncogenic stress and transformation in older mice and also observed in aged humans with Metabolic dysfunction-Associated Steatohepatitis (MASH). We determined that Stat1 is both necessary and sufficient for the age specific elevated ISG expression in old wild type mice. Remarkably, inhibiting Jak/Stat signaling alongside ectopic c-Myc expression led to high-grade hepatocyte dysplasia and tumor formation, selectively in aged mice. Together, these results suggest that an aged liver is in a state of “precarious balance”, due to concurrent activation of oncogenic and tumor suppressor pathways, but protected against neoplastic progression by IFN-signaling. Age-dependent activation of IFN signaling has been observed in many tissues and recent studies have demonstrated its detrimental consequences on aging, raising the question as to why IFN-signaling is activated during aging. We propose that aged tissues are intrinsically at higher risk of cancer and age-dependent activation of IFN-signaling is an adaptive process to protect from tumorigenesis, but one that also has maladaptive consequences.

Dataset Information

FOXA1 overexpression suppresses interferon signaling and immune response in cancer.

Publications

FOXA1 overexpression suppresses interferon signaling and immune response in cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets