Flightless I Homolog Represses Prostate Cancer Progression through Targeting Androgen Receptor Signaling

Wang, Tao; Song, Wen; Chen, Yuan; Chen, Ruibao; Liu, Zhuo; Wu, Liang; Li, Mingchao; Yang, Jun; Wang, Liang; Liu, Jihong; Ye, Zhangqun; Wang, Chenguang; Chen, Ke

doi:10.1158/1078-0432.ccr-15-1632

Cited by 25 publications

(33 citation statements)

References 50 publications

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“…The lentiviral particles containing GV341-FLAG-YBX1 and GV348-HA-FLII were purchased from Shanghai GeneChem and used to infect cells according to the manufacturer's recommendations. The p-FLAG-YBX1-CSD, p-FLAG-YBX1-C-term, p-HA-FLII-LRR, and p-HA-FLII-GLD plasmids were kindly provided by Professor Chen [22]. Lipofectamine 2000 was used for plasmid transfection as recommended by the manufacturer.…”

Section: Methodsmentioning

confidence: 99%

“…1a-b. Our previous studies showed that FLII enhanced the sensitivity of CRPC cells to enzalutamide treatment [22]. To explore the mechanism, we reintroduced FLII into C4-2-R, C4-2 and PC-3 cells.…”

Section: Flii Expression Is Negatively Correlated With Pd-l1mentioning

confidence: 99%

“…Mammalian FLII has been reported to function as a coactivator via nuclear hormone receptor signaling, including signaling via estrogen receptors and thyroid hormone receptors [21]. We have previously discovered that FLII, as a cosuppressor of AR, can antagonize the DHT-induced nuclear localization of AR, thereby reversing the tolerance of traditional neo-endocrine therapy (bicalutamide) and enhancing the sensitivity to neoendocrine therapy (enzalutamide) [22]. However, the role and mechanism of FLII in enzalutamideresistant CRPC remain unclear.…”

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confidence: 99%

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Flightless I Homolog Reverses Neo-Endocrine Therapy Resistance through YBX1/PD-L1 Axis Mediated-Immune Evasion in Prostate Cancer

Ruan¹,

Bao²,

Zhen³

et al. 2020

Preprint

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Background: Tumor cells can evade immune surveillance and immune killing effects during neo-endocrine therapy resistance, but the mechanisms that induce this phenomenon are still unclear. Flightless I homolog (FLII) functions as a coregulator of transcription factors in malignancies. Here, we aim to identify the functions and mechanisms of FLII-mediated neo-endocrine therapy resistance and immune evasion in prostate cancer (PCa).Methods: Bioinformatics analysis and PCa tissue microarray were used to assess the correlation between FLII and the immune checkpoint PD-L1. Immunoprecipitation (IP) and chromatin immunoprecipitation (ChIP) were used to investigate the regulation of PD-L1 expression by FLII. Enzyme-linked immunosorbent assay (ELISA) was used to study the effect of FLII on cytokine secretion. The number of effector T cells and immunosuppressive lymphocytes was detected by flow cytometry (FCM).Results: FLII was negatively correlated with the expression of PD-L1 in PCa. Mechanistic studies demonstrated that FLII physically interacted with YBX1 to inhibit the nuclear localization of YBX1 and thereby suppressed the transcriptional expression of PD-L1 in enzalutamide-resistant tumors. Restoration of FLII expression reversed neo-endocrine therapy resistance by activating the T cell response in the tumor microenvironment mediated by partial inhibition of the YBX1/PD-L1 pathway. The reversal of neo-endocrine therapy resistance and immune evasion was mediated by the proliferation of effector CD8+ T cells and inhibition of the infiltration of regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment.Conclusions: FLII inhibits tumor progression in part through repressing YBX1/PD-L1-mediated immune evasion. Combination therapy with FLII and neo-endocrine therapy may improve the benefits in prostate cancer patients and avoid immune evasion.

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Section: Methodsmentioning

confidence: 99%

Section: Flii Expression Is Negatively Correlated With Pd-l1mentioning

confidence: 99%

mentioning

confidence: 99%

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Flightless I Homolog Reverses Neo-Endocrine Therapy Resistance through YBX1/PD-L1 Axis Mediated-Immune Evasion in Prostate Cancer

Ruan¹,

Bao²,

Zhen³

et al. 2020

Preprint

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“…Tissue samples A collection of 40 different kinds of fresh-frozen prostate cancer tumor specimens and 20 tumor normal adjacent tissues were from Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. All tumor samples were collected immediately after the surgical removal and snap-frozen in liquid nitrogen [12].…”

Section: Cell Culture Plasmid Construction Reporter Genes Reagentsmentioning

confidence: 99%

MiR-195/-16 Family Enhances Radiotherapy via T Cell Activation in the Tumor Microenvironment by Blocking the PD-L1 Immune Checkpoint

Tao

Ruan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Radiotherapy is the standard treatment option for advanced prostate cancer. Unfortunately, despite significant advances in radiation delivery, prostate cancer radioresistance occurs in a large proportion of patients undergoing radiotherapy. As a way to enhance radiotherapy effectiveness, research advances into the mechanisms regulating the immune response have revived interest in combination radiation and immune-based therapies. Methods: miR-195/-16 family and PD-L1 levels were analyzed in samples from a GSE21032 data set. Kaplan-Meier analysis was used to evaluate the difference in biochemical recurrence-free survival associated with miR-195 and miR-16 expression. qRT-PCR and western blot were used to evaluate the miR-195, miR-16 and PD-L1 expression. Then, we used bioinformatics analysis and luciferase reporter assay to predict and confirm the miR-195 and miR-16 target gene. Finally, we elucidate the miR-195 and miR-16 function on immune evasion in the DU145/T cell co-culture model and syngeneic mouse model treated with radiotion through qRT-PCR, western blot, Flow cytometry and ELISA. Results: High levels of miR-195 and miR-16 were positively correlated with the biochemical recurrence-free survival of prostate cancer patients. miR-195 and miR-16 were inversely correlated with PD-L1, PD-1, CD80 and CTLA-4 expression. Further mechanistic investigations revealed that miR-195 and miR-16 inhibited PD-L1 expression. Additionally, restoration of miR-195 and miR-16 expression enhanced radiotherapy via T cell activation in the tumor microenvironment by blocking PD-L1 expression. This synergistic effect of immunotherapy and radiotherapy was associated with the proliferation of functional cytotoxic CD8+ T cells and inhibition of myeloid-derived suppressor cells and regulatory T cells. Conclusions: Our data revealbiological and functional interactions between immunotherapy and radiotherapy through the miR-195/-16 family regulatory cascade.

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“…Moreover, FliI interacts with caspase-11, and recruits it into the Triton X-100 insoluble actin bundle fraction (termed as TI), resulting in the inhibition of inflammasome activation (16,17). Physical interaction of FliI with several transcription factors, including androgen receptor (AR) and carbohydrate responsive element-binding protein (ChREBP), can regulate glucose metabolism and cell proliferation of prostate or colorectal cancer cells via modulation of their transcriptional activities (18,19). Therefore, it is likely that FliI functions differentially through interaction with different binding partners.…”

Section: Introductionmentioning

confidence: 99%

Flightless-I Blocks p62-Mediated Recognition of LC3 to Impede Selective Autophagy and Promote Breast Cancer Progression

Hou

Chen

et al. 2018

Cancer Research

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p62 is a receptor that facilitates selective autophagy by interacting simultaneously with cargoes and LC3 protein on the autophagosome to maintain cellular homeostasis. However, the regulatory mechanism(s) behind this process and its association with breast cancer remain to be elucidated. Here, we report that Flightless-I (FliI), a novel p62-interacting protein, promotes breast cancer progression by impeding selective autophagy. FliI was highly expressed in clinical breast cancer samples, and heterozygous deletion of FliI retarded the development of mammary tumors in PyVT mice. FliI induced p62-recruited cargoes into Triton X-100 insoluble fractions (TI) to form aggregates, thereby blocking p62 recognition of LC3 and hindering p62-dependent selective autophagy. This function of Flil was reinforced by Akt-mediated phosphorylation at Ser436 and inhibited by phosphorylation of Ulk1 at Ser64. Obstruction of autophagic clearance of p62-recruited cargoes by FliI was associated with the accumulation of oxidative damage on proteins and DNA, which could contribute to the development of cancer. Heterozygous knockout of FliI facilitated selectively autophagic clearance of aggregates, abatement of ROS levels, and protein oxidative damage, ultimately retarding mammary cancer progression. In clinical breast cancer samples, Akt-mediated phosphorylation of FliI at Ser436 negatively correlated with long-term prognosis, while Ulk1-induced FliI phosphorylation at Ser64 positively correlated with clinical outcome. Together, this work demonstrates that FliI functions as a checkpoint protein for selective autophagy in the crosstalk between FliI and p62-recruited cargoes, and its phosphorylation may serve as a prognostic marker for breast cancer. Flightless-I functions as a checkpoint protein for selective autophagy by interacting with p62 to block its recognition of LC3, leading to tumorigenesis in breast cancer..

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Flightless I Homolog Represses Prostate Cancer Progression through Targeting Androgen Receptor Signaling

Cited by 25 publications

References 50 publications

Flightless I Homolog Reverses Neo-Endocrine Therapy Resistance through YBX1/PD-L1 Axis Mediated-Immune Evasion in Prostate Cancer

Flightless I Homolog Reverses Neo-Endocrine Therapy Resistance through YBX1/PD-L1 Axis Mediated-Immune Evasion in Prostate Cancer

MiR-195/-16 Family Enhances Radiotherapy via T Cell Activation in the Tumor Microenvironment by Blocking the PD-L1 Immune Checkpoint

Flightless-I Blocks p62-Mediated Recognition of LC3 to Impede Selective Autophagy and Promote Breast Cancer Progression

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