Zfhx3 is essential for progesterone/progesterone receptor signaling to drive ductal side-branching and alveologenesis in mouse mammary glands

Ma, Guansheng; Gao, Ang; Yang, Yinan; He, Yuan; Zhang, Xi; Zhang, Baotong; Zhang, Zhiqian; Li, Mei; Fu, Xing; Zhao, Dan; Wu, Rui; Qi, Leilei; Hu, Qingxia; Li, Juan; Fu, Liwei; Zhu, Zhengmao; Dong, Jin‐Tang

doi:10.1016/j.jgg.2019.03.003

Cited by 14 publications

(18 citation statements)

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“…While SUMOylation at K2806 is crucial for the function of ZFHX3 in the proliferation of some breast cancer cell lines and this SUMOylation site is evolutionally conserved among different animal species, it is unknown whether the promoting effect of SUMOylated ZFHX3 on cell proliferation is also there for normal mammary epithelial cells, where Zfhx3 is essential for the progesterone signaling to induce ductal cell proliferation during side branching (34). In addition, it is also unknown whether SUMOylation modulates the function of ZFHX3 in prostate cancer cells, where ZFHX3 clearly possesses a tumor suppressor activity based on its frequent inactivating mutations in advanced human prostate cancer and the induction of neoplastic lesions by its deletion (35).…”

Section: Discussionmentioning

confidence: 99%

“…ZFHX3 is rarely mutated in breast cancer (29), and ZFHX3 interacts with estrogen receptor alpha to modulate gene expression and cell proliferation in breast cancer cells (30,31). During postnatal development of mouse mammary glands, Zfhx3 is essential for the progesterone signaling to induce cell proliferation, side branching, and alveologenesis (32)(33)(34). ZFHX3 has also been implicated in other types of cancers including gastric, cervical, and head and neck (35).…”

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confidence: 99%

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SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation

Fang

Liu

et al. 2020

Journal of Biological Chemistry

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SUMOylation is a posttranslational modification (PTM) at a lysine residue and is crucial for the proper functions of many proteins, particularly of transcription factors, in various biological processes. Zinc finger homeobox 3 (ZFHX3), also known as AT motif-binding factor 1 (ATBF1), is a large transcription factor that is active in multiple pathological processes, including atrial fibrillation and carcinogenesis, and in circadian regulation and development. We have previously demonstrated that ZFHX3 is SUMOylated at three or more lysine residues. Here, we investigated which enzymes regulate ZFHX3 SUMOylation and whether SUMOylation modulates ZFHX3 stability and function. We found that SUMO1, SUMO2, and SUMO3 each are conjugated to ZFHX3. Multiple lysine residues in ZFHX3 were SUMOylated, but Lys-2806 was the major SUMOylation site, and we also found that it is highly conserved among ZFHX3 orthologs from different animal species. Using molecular analyses, we identified the enzymes that mediate ZFHX3 SUMOylation; these included SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme; SUMO-conjugating enzyme UBC9 (UBC9), an E2-conjugating enzyme; and protein inhibitor of activated STAT2 (PIAS2), an E3 ligase. Multiple analyses established that both SUMO-specific peptidase 1 (SENP1) and SENP2 deSUMOylate ZFHX3. SUMOylation at Lys-2806 enhanced ZFHX3 stability by interfering with its ubiquitination and proteasomal degradation. Functionally, Lys-2806 SUMOylation enabled ZFHX3-mediated cell proliferation and xenograft tumor growth of the MDA-MB-231 breast cancer cell line. These findings reveal the enzymes involved in, and the functional consequences of, ZFHX3 SUMOylation, insights that may help shed light on ZFHX3's roles in various cellular and pathophysiological processes.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation

Fang

Liu

et al. 2020

Journal of Biological Chemistry

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“…ZFHX3 has been suspected of playing a role in breast carcinogenesis because it interacts with ER and PR to regulate gene expression, cell proliferation, cell differentiation, and mammary gland development [ 15 , 20 ]. Both ER and PR have been well implicated in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…In pubertal mouse mammary glands, Zfhx3 inhibits cell proliferation and ductal elongation and bifurcation [ 14 ]. However, during reproduction, Zfhx3 promotes mammary epithelial cell proliferation, side branching, alveologenesis, and lactogenic differentiation [ 15 , 16 ]. Although higher levels of ZFHX3-A mRNA in breast cancer cells are associated with better prognosis, such as smaller tumor size and reduced lymph node metastasis in breast cancer [ 17 ], ZFHX3 is transcriptionally upregulated by both the estrogen/ER and progesterone (Pg)/PR signaling pathways via the binding of ER and PR, respectively, to the ZFHX3 promoter [ 15 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, during reproduction, Zfhx3 promotes mammary epithelial cell proliferation, side branching, alveologenesis, and lactogenic differentiation [ 15 , 16 ]. Although higher levels of ZFHX3-A mRNA in breast cancer cells are associated with better prognosis, such as smaller tumor size and reduced lymph node metastasis in breast cancer [ 17 ], ZFHX3 is transcriptionally upregulated by both the estrogen/ER and progesterone (Pg)/PR signaling pathways via the binding of ER and PR, respectively, to the ZFHX3 promoter [ 15 , 18 , 19 ]. Combining ER and PR’s roles in breast cancer and their interactions with ZFHX3 [ 14 , 15 , 20 ], it is likely that ZFHX3 plays a role in breast carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

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ZFHX3 Promotes the Proliferation and Tumor Growth of ER-Positive Breast Cancer Cells Likely by Enhancing Stem-Like Features and MYC and TBX3 Transcription

Dong

et al. 2020

Cancers

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Breast cancer is a common malignancy, but the understanding of its cellular and molecular mechanisms is limited. ZFHX3, a transcription factor with many homeodomains and zinc fingers, suppresses prostatic carcinogenesis but promotes tumor growth of liver cancer cells. ZFHX3 regulates mammary epithelial cells’ proliferation and differentiation by interacting with estrogen and progesterone receptors, potent breast cancer regulators. However, whether ZFHX3 plays a role in breast carcinogenesis is unknown. Here, we found that ZFHX3 promoted the proliferation and tumor growth of breast cancer cells in culture and nude mice; and higher expression of ZFHX3 in human breast cancer specimens was associated with poorer prognosis. The knockdown of ZFHX3 in ZFHX3-high MCF-7 cells decreased, and ZFHX3 overexpression in ZFHX3-low T-47D cells increased the proportion of breast cancer stem cells (BCSCs) defined by mammosphere formation and the expression of CD44, CD24, and/or aldehyde dehydrogenase 1. Among several transcription factors that have been implicated in BCSCs, MYC and TBX3 were transcriptionally activated by ZFHX3 via promoter binding, as demonstrated by luciferase-reporter and ChIP assays. These findings suggest that ZFHX3 promotes breast cancer cells’ proliferation and tumor growth likely by enhancing BCSC features and upregulating MYC, TBX3, and others.

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Intratumoral injection of caerin 1.1 and 1.9 peptides increases the efficacy of vaccinated TC‐1 tumor‐bearing mice with PD‐1 blockade by modulating macrophage heterogeneity and the activation of CD8⁺ T cells in the tumor microenvironment

Yang

et al. 2021

Clin & Trans Imm

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Objectives Developing a vaccine formula that alters the tumor‐infiltrating lymphocytes to be more immune active against a tumor is key to the improvement of clinical responses to immunotherapy. Here, we demonstrate that, in conjunction with E7 antigen‐specific immunotherapy, and IL‐10 and PD‐1 blockade, intratumoral administration of caerin 1.1/1.9 peptides improves TC‐1 tumor microenvironment (TME) to be more immune active than injection of a control peptide. Methods We compared the survival time of vaccinated TC‐1 tumor‐bearing mice with PD‐1 and IL‐10 blockade, in combination with a further injection of caerin 1.1/1.9 or control peptides. The tumor‐infiltrating haematopoietic cells were examined by flow cytometry. Single‐cell transcriptomics and proteomics were used to quantify changes in cellular activity across different cell types within the TME. Results The injection of caerin 1.1/1.9 increased the efficacy of vaccinated TC‐1 tumor‐bearing mice with anti‐PD‐1 treatment and largely expanded the populations of macrophages and NK cells with higher immune activation level, while reducing immunosuppressive macrophages. More activated CD8 + T cells were induced with higher populations of memory and effector‐memory CD8 + T subsets. Computational integration of the proteome with the single‐cell transcriptome supported activation of Stat1 ‐modulated apoptosis and significant reduction in immune‐suppressive B‐cell function following caerin 1.1 and 1.9 treatment. Conclusions Caerin 1.1/1.9‐containing treatment results in improved antitumor responses. Harnessing the novel candidate genes preferentially enriched in the immune active cell populations may allow further exploration of distinct macrophages, T cells and their functions in TC‐1 tumors.

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Zfhx3 is essential for progesterone/progesterone receptor signaling to drive ductal side-branching and alveologenesis in mouse mammary glands

Cited by 14 publications

References 53 publications

SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation

SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation

ZFHX3 Promotes the Proliferation and Tumor Growth of ER-Positive Breast Cancer Cells Likely by Enhancing Stem-Like Features and MYC and TBX3 Transcription

Intratumoral injection of caerin 1.1 and 1.9 peptides increases the efficacy of vaccinated TC‐1 tumor‐bearing mice with PD‐1 blockade by modulating macrophage heterogeneity and the activation of CD8⁺ T cells in the tumor microenvironment

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Zfhx3 is essential for progesterone/progesterone receptor signaling to drive ductal side-branching and alveologenesis in mouse mammary glands

Cited by 14 publications

References 53 publications

SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation

SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation

ZFHX3 Promotes the Proliferation and Tumor Growth of ER-Positive Breast Cancer Cells Likely by Enhancing Stem-Like Features and MYC and TBX3 Transcription

Intratumoral injection of caerin 1.1 and 1.9 peptides increases the efficacy of vaccinated TC‐1 tumor‐bearing mice with PD‐1 blockade by modulating macrophage heterogeneity and the activation of CD8+ T cells in the tumor microenvironment

Contact Info

Product

Resources

About

Intratumoral injection of caerin 1.1 and 1.9 peptides increases the efficacy of vaccinated TC‐1 tumor‐bearing mice with PD‐1 blockade by modulating macrophage heterogeneity and the activation of CD8⁺ T cells in the tumor microenvironment