FOXA1 overexpression suppresses interferon signaling and immune response in cancer

He, Yundong; Wang, Liguo; Wei, Ting; Xiao, Yu‐Tian; Sheng, Haoyue; Su, Hengchuan; Hollern, Daniel P.; Ma, Jian; Wen, Simeng; Xie, Hongyan; Yan, Yuqian; Pan, Yunqian; Hou, Xiaonan; Tang, Xiaojia; Suman, Vera J.; Carter, Jodi M.; Weinshilboum, Richard M.; Wang, Liewei; Kalari, Krishna R.; Weroha, S. John; Bryce, Alan H.; Boughey, Judy C.; Dong, Haidong; Perou, Charles M.; Ye, Dingwei; Goetz, Matthew P.; Ren, Shancheng; Huang, Haojie

doi:10.1172/jci147025

Cited by 53 publications

(41 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…S6E). This suggests that the upregulation of these genes upon FOXA1 knockdown is independent of FOXA1 binding of their regulatory elements, in agreement with recent work showing that FOXA1 directly binds and inhibits the STAT2 protein to dampen inflammation in a chromatin-independent manner [49]. Interestingly, if FOXA1 knock down triggered interferon response in both Luminal and Basal models, its depletion affected the Luminal network of co-regulated TFs only in RT112 cells and not in SCaBER (Fig.…”

Section: Foxa1 Regulates Inflammation and Cellular Identitysupporting

confidence: 91%

Epigenomic mapping identifies a super-enhancer repertoire that regulates cell identity in bladder cancers through distinct transcription factor networks

Neyret‐Kahn

Fontugne

Meng

et al. 2022

Preprint

View full text Add to dashboard Cite

Background: Muscle-invasive bladder cancer is a common aggressive disease with unmet clinical needs. Recent work established a set of consensus bladder cancer transcriptomic subtypes that distinguishes the cell identity of bladder cancers for improved diagnosis and treatment. However, how these distinct subtypes are regulated remains unclear. Given the link between super-enhancers and the regulation of cell identity, we hypothesized that epigenetic activation of distinct super-enhancers could drive the transcriptional programs of the various bladder cancer subtypes. Results: Through integrated RNA sequencing and epigenomic profiling of histone marks (H3K27ac, H3K27me3, H3K9me3) in a diverse panel of 15 primary bladder tumours, seven bladder cancer cell lines, and two primary cultures from normal human urothelia, we established the first integrated epigenetic map of bladder cancer and demonstrate the link between bladder cancer subtype and epigenetic control. Through H3K27ac analysis, we identify the repertoire of activated super-enhancers in bladder cancer that distinguish molecular subtypes. Building on these findings, we reveal the super-enhancer-regulated networks of candidate master transcription factors for Luminal and Basal bladder cancer subgroups. We find that FOXA1, a key pioneer factor in Luminal bladder cancers identified in our Luminal transcription factor network, binds subgroup-specific bladder super-enhancers and correlates with their activation. Furthermore, CRISPR-Cas9 inactivating mutation of FOXA1 triggers a shift from Luminal to Basal cell identity. This shift is accompanied by an overexpression of ZBED2, one of the newly identified transcriptional regulators in the Basal-specific transcription factor network. Finally, we show that both FOXA1 and ZBED2 play concordant roles in preventing inflammatory response in bladder cancer cells through STAT2 inhibition and promote cancer cell survival. Conclusions: Overall, our study provides new data for understanding epigenetic regulation of muscle-invasive bladder cancer and identifies a coregulated network of super-enhancers and associated transcription factors as new potential targets for the treatment of this aggressive disease.

show abstract

Section: Foxa1 Regulates Inflammation and Cellular Identitysupporting

confidence: 91%

Epigenomic mapping identifies a super-enhancer repertoire that regulates cell identity in bladder cancers through distinct transcription factor networks

Neyret‐Kahn

Fontugne

Meng

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Interferon (INF) signaling pathways (including INFα, INFβ, and INFγ) are required for the anti-tumor immune response and subsequent cancer cell death, and tumors with low INF activity are often resistant to immune checkpoint inhibitor therapies [160,161]. A recent study revealed that FOXA1 expression is negatively correlated with interferon activity and the INF-response gene expression signature in luminal breast cancer, suggesting that FOXA1 suppresses the immune response in this disease [162]. Supporting this, neoadjuvant chemotherapy-treated tumors that express high levels of FOXA1 have low INF activity, reduced pathological response to chemotherapy, and decreased immune response [162].…”

Section: Foxa1 Expressed In Tumor Cells Suppresses the Tumor Immune Responsementioning

confidence: 99%

“…A recent study revealed that FOXA1 expression is negatively correlated with interferon activity and the INF-response gene expression signature in luminal breast cancer, suggesting that FOXA1 suppresses the immune response in this disease [162]. Supporting this, neoadjuvant chemotherapy-treated tumors that express high levels of FOXA1 have low INF activity, reduced pathological response to chemotherapy, and decreased immune response [162]. Transcriptional induction of INF and its target genes is mainly dependent on STAT (signal transducer and activator of transcription) signaling that is independent of ER binding [163].…”

Section: Foxa1 Expressed In Tumor Cells Suppresses the Tumor Immune Responsementioning

confidence: 99%

“…Third, NR crosstalk can reprogram FOXA1 chromatin binding, which can also contribute to therapy resistance and compensatory pathway activation [58,[148][149][150]154,156,158,168,169]. Increased FOXA1 expression can also suppress the tumor immune response, which is associated with worse patient outcomes [162,167,170]. Lastly, genetic approaches inhibiting FOXA1 expression within the contexts mentioned above result in decreased tumor cell proliferation, reversal of therapy resistance, and increased the tumor immune response.…”

Section: Foxa1 As a Therapeutic Target In Breast Cancermentioning

confidence: 99%

See 1 more Smart Citation

FOXA1: A Pioneer of Nuclear Receptor Action in Breast Cancer

Seachrist

Anstine

Keri

2021

Cancers

View full text Add to dashboard Cite

The pioneering function of FOXA1 establishes estrogen-responsive transcriptomes in luminal breast cancer. Dysregulated FOXA1 chromatin occupancy through focal amplification, mutation, or cofactor recruitment modulates estrogen receptor (ER) transcriptional programs and drives endocrine-resistant disease. However, ER is not the sole nuclear receptor (NR) expressed in breast cancers, nor is it the only NR for which FOXA1 serves as a licensing factor. Receptors for androgens, glucocorticoids, and progesterone are also found in the majority of breast cancers, and their functions are also impacted by FOXA1. These NRs interface with ER transcriptional programs and, depending on their activation level, can reprogram FOXA1-ER cistromes. Thus, NR interplay contributes to endocrine therapy response and resistance and may provide a vulnerability for future therapeutic benefit in patients. Herein, we review what is known regarding FOXA1 regulation of NR function in breast cancer in the context of cell identity, endocrine resistance, and NR crosstalk in breast cancer progression and treatment.

show abstract

“…The overexpression of the transcription factor FOXA1, which directly binds the STAT2 DNA-binding domain (DBD), impedes the STAT2 related expression of IFN-signaling and antigen presentation machinery (APM) genes. The authors suggest that FOXA1 overexpression could be a predictor of therapy resistance to immune-and chemotherapy in prostate, breast, and bladder cancer patients [98].…”

Section: Opposing Effects Of Ifn-is In Disease Progression and Resistance To Therapymentioning

confidence: 99%

Actin Cytoskeleton Dynamics and Type I IFN-Mediated Immune Response: A Dangerous Liaison in Cancer?

Trono

Tocci²,

Musella

et al. 2021

Biology

View full text Add to dashboard Cite

Chronic viral infection and cancer are closely inter-related and are both characterized by profound alteration of tissue homeostasis. The actin cytoskeleton dynamics highly participate in tissue homeostasis and act as a sensor leading to an immune-mediated anti-cancer and anti-viral response. Herein we highlight the crucial role of actin cytoskeleton dynamics in participating in a viral mimicry activation with profound effect in anti-tumor immune response. This still poorly explored field understands the cytoskeleton dynamics as a platform of complex signaling pathways which may regulate Type I IFN response in cancer. This emerging network needs to be elucidated to identify more effective anti-cancer strategies and to further advance the immuno-oncology field which has revolutionized the cancer treatment. For a progress to occur in this exciting arena we have to shed light on actin cytoskeleton related pathways and immune response. Herein we summarize the major findings, considering the double sword of the immune response and in particular the role of Type I IFN pathways in resistance to anti-cancer treatment.

show abstract

FOXA1 overexpression suppresses interferon signaling and immune response in cancer

Cited by 53 publications

References 65 publications

Epigenomic mapping identifies a super-enhancer repertoire that regulates cell identity in bladder cancers through distinct transcription factor networks

Epigenomic mapping identifies a super-enhancer repertoire that regulates cell identity in bladder cancers through distinct transcription factor networks

FOXA1: A Pioneer of Nuclear Receptor Action in Breast Cancer

Actin Cytoskeleton Dynamics and Type I IFN-Mediated Immune Response: A Dangerous Liaison in Cancer?

Contact Info

Product

Resources

About