Phosphorylation of HSF1 by PIM2 Induces PD-L1 Expression and Promotes Tumor Growth in Breast Cancer

Yang, Tingting; Ren, Chune; Lü, Chao; Qiao, Pengyun; Han, Xue; Wang, Li; Wang, Dan; Lv, Shijun; Sun, Yonghong; Yu, Zhenhai

doi:10.1158/0008-5472.can-19-0063

Cited by 70 publications

(53 citation statements)

References 45 publications

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“…Taken together, β-catenin suppressed the biogenesis of miR455-3p to allow METTL3 binding for m6A modification of HSF1 mRNA, thus stimulating HSF1 mRNA translation. In cancer cells, HSF1 can drive a transcriptional program distinct from heat shock response to support malignant phenotypes [ 15 , 43 ]. For instance, HSF1 can drive the transcription of PDK3 (Pyruvate Dehydrogenase Kinase 3) to promote glycolysis in chemo-resistant cancer cells [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

β-catenin represses miR455-3p to stimulate m6A modification of HSF1 mRNA and promote its translation in colorectal cancer

Song

Feng

et al. 2020

Mol Cancer

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Background Heat shock transcription factor1 (HSF1) was overexpressed to promote glutaminolysis and activate mTOR in colorectal cancer (CRC). Here, we investigated the mechanism for cancer-specific overexpression of HSF1. Methods HSF1 expression was analyzed by chromatin immunoprecipitation, qRT-PCR, immunohistochemistry staining and immunoblotting. HSF1 translation was explored by polysome profiling and nascent protein analysis. Biotin pulldown and m6A RNA immunoprecipitation were applied to investigate RNA/RNA interaction and m6A modification. The relevance of HSF1 to CRC was analyzed in APC min/+ and APC min/+ HSF1 +/− mice. Results HSF1 expression and activity were reduced after the inhibition of WNT/β-catenin signaling by pyrvinium or β-catenin knockdown, but elevated upon its activation by lithium chloride (LiCl) or β-catenin overexpression. There are much less upregulated genes in HSF1-KO MEF treated with LiCl when compared with LiCl-treated WT MEF. HSF1 protein expression was positively correlated with β-catenin expression in cell lines and primary tissues. After β-catenin depletion, HSF1 mRNA translation was impaired, accompanied by the reduction of its m6A modification and the upregulation of miR455-3p, which can interact with 3′-UTR of HSF1 mRNA to repress its translation. Interestingly, inhibition of miR455-3p rescued β-catenin depletion-induced reduction of HSF1 m6A modification and METTL3 interaction. Both the size and number of tumors were significantly reduced in APC min/+ mice when HSF1 was genetically knocked-out or chemically inhibited. Conclusions β-catenin suppresses miR455-3p generation to stimulate m6A modification and subsequent translation of HSF1 mRNA. HSF1 is important for β-catenin to promote CRC development. Targeting HSF1 could be a potential strategy for the intervention of β-catenin-driven cancers.

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Section: Discussionmentioning

confidence: 99%

β-catenin represses miR455-3p to stimulate m6A modification of HSF1 mRNA and promote its translation in colorectal cancer

Song

Feng

et al. 2020

Mol Cancer

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“…It has recently been reported that the phosphorylation of HSF1 by PIM2, which interrupts the binding of the E3 ligase to HSF1, enhances the stability of HSF1, and promotes HSF1 binding to PD-L1 promoter. The resulting overexpression of PD-L1 enhances the breast cancer growth and tumorigenesis in vitro and in vivo [89]. In addition, Family with sequence similarity member C (FAM3C) is a commonly known interleukin-like EMT inducer, and it has been demonstrated that the upregulation of HSF1 is the underlying mechanism of FAM3C-mediated tumorigenesis [90].…”

Section: Role Of Hsf1 In Cancer Developmentmentioning

confidence: 99%

Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

Yun

Kim

Lim

et al. 2019

Cells

201

158

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Heat shock proteins (HSPs) constitute a large family of molecular chaperones classified by their molecular weights, and they include HSP27, HSP40, HSP60, HSP70, and HSP90. HSPs function in diverse physiological and protective processes to assist in maintaining cellular homeostasis. In particular, HSPs participate in protein folding and maturation processes under diverse stressors such as heat shock, hypoxia, and degradation. Notably, HSPs also play essential roles across cancers as they are implicated in a variety of cancer-related activities such as cell proliferation, metastasis, and anti-cancer drug resistance. In this review, we comprehensively discuss the functions of HSPs in association with cancer initiation, progression, and metastasis and anti-cancer therapy resistance. Moreover, the potential utilization of HSPs to enhance the effects of chemo-, radio-, and immunotherapy is explored. Taken together, HSPs have multiple clinical usages as biomarkers for cancer diagnosis and prognosis as well as the potential therapeutic targets for anti-cancer treatment.

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“…The beads were washed at least 5 times using IP buffer, and then used for subsequent experiments. The indicated proteins were expressed in E.coli BL21 (DE3), and GST-pull down assay was performed as described previously 17 .…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, various special inhibitors, including JP11646, SMI-4a and SGI-1776, have been developed for PIM kinase activity and have been used for clinical treatment 19 - 21 . Recently, we found that PIM2 acts as an oncogene in breast cancer 15 , 17 , 22 , but the underlying mechanism of its oncogene function remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Fructose-1, 6-bisphosphatase 1 interacts with NF-κB p65 to regulate breast tumorigenesis via PIM2 induced phosphorylation

Lü¹,

Ren²,

Yang³

et al. 2020

Theranostics

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Rationale: Fructose-1, 6-bisphosphatase 1 (FBP1), a rate-limiting enzyme in gluconeogenesis, was recently shown to be a tumor suppressor and could mediate the activities of multiple transcriptional factors via its non-canonical functions. However, the underlying mechanism of posttranscriptional modification on the non-canonical functions of FBP1 remains elusive. Methods: We employed immunoaffinity purification to identify binding partner(s) and used co-immunoprecipitation to verify their interactions. Kinase reaction was used to confirm PIM2 could phosphorylate FBP1. Overexpression or knockdown proteins were used to assess the role in modulating p65 protein stability. Mechanistic analysis was involved in protein degradation and polyubiquitination assays. Nude mice and PIM2-knockout mice was used to study protein functions in vitro and in vivo . Results: Here, we identified Proviral Insertion in Murine Lymphomas 2 (PIM2) as a new binding partner of FBP1, which could phosphorylate FBP1 on Ser144. Surprisingly, phosphorylated FBP1 Ser144 abrogated its interaction with NF-κB p65, promoting its protein stability through the CHIP-mediated proteasome pathway. Furthermore, phosphorylation of FBP1 on Ser144 increased p65 regulated PD-L1 expression. As a result, phosphorylation of FBP1 on Ser144 promoted breast tumor growth in vitro and in vivo . Moreover, the levels of PIM2 and pSer144-FBP1 proteins were positively correlated with each other in human breast cancer and PIM2 knockout mice. Conclusions: Our findings revealed that phosphorylation noncanonical FBP1 by PIM2 was a novel regulator of NF-κB pathway, and highlights PIM2 inhibitors as breast cancer therapeutics.

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Phosphorylation of HSF1 by PIM2 Induces PD-L1 Expression and Promotes Tumor Growth in Breast Cancer

Cited by 70 publications

References 45 publications

β-catenin represses miR455-3p to stimulate m6A modification of HSF1 mRNA and promote its translation in colorectal cancer

β-catenin represses miR455-3p to stimulate m6A modification of HSF1 mRNA and promote its translation in colorectal cancer

Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

Fructose-1, 6-bisphosphatase 1 interacts with NF-κB p65 to regulate breast tumorigenesis via PIM2 induced phosphorylation

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