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YEATS2 regulates the activation of TAK1/NF-κB pathway and is critical for pancreatic ductal adenocarcinoma cell survival

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Abstract

The prognosis of pancreatic ductal adenocarcinoma (PDAC) is poor despite diagnostic progress and new chemotherapeutic regimens. Constitutive activation of NF-κB is frequently observed in PDAC. In this study, we found that YEATS2, a scaffolding protein of ATAC complex, was highly expressed in human PDAC. Depletion of YEATS2 reduced the growth, survival, and tumorigenesis of PDAC cells. The binding of YEATS2 is crucial for maintaining TAK1 activation and NF-κB transcriptional activity. Of importance, our results reveal that YEATS2 promotes NF-κB transcriptional activity through modulating TAK1 abundance and directly interacting with NF-κB as a co-transcriptional factor.

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Data availability

The authors declare that the data supporting the findings of this study are available within the article and its supplementary information files.

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Acknowledgements

We are grateful to the pzlink-yeats2 plasmid provided by Haitao Li at Tsinghua University.

Funding

This work was supported by the Natural Science Foundation of China (81502304, 81903873), Natural Science Foundation of Zhejiang Province (LQ19H160002, LQ18H160001), Medical and Health Technology Projects of Zhejiang Province (2017KY696, 2019PY089), Chinese Medicine Science Foundation of Zhejiang Province (2021ZB328), Quzhou Technology Projects, China (2018K20).

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Authors and Affiliations

  1. Core Facility, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, 324000, Quzhou, China

    Hao Sheng, Fang Zheng, Tian Lan, Si-wei Wang, Yuan-yuan Weng, Li-feng Xu & Feng Zhang

  2. The Second Affiliated Hospital (Jiande Branch), Zhejiang University School of Medicine, Jiande, Hangzhou, Zhejiang, China

    Hao Sheng

  3. Zhejiang University School of Medicine, Hangzhou, China

    Hao Sheng & Feng Zhang

  4. Zhejiang Chinese Medical University, Hangzhou, China

    Hang-fei Chen, Chun-yi Xu & Feng Zhang

  5. Department of Clinical Laboratory, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou, China

    Yuan-yuan Weng

Authors
  1. Hao Sheng
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  3. Tian Lan
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Contributions

Participated in research design: F. Zhang

Conducted experiments: H. Sheng, F. Zheng, H.F. Chen, C.Y. Xu, T. Lan, S.W. Wang, Y.Y. Weng

Performed data analysis: F. Zhang, H. Sheng

Wrote or contributed to the writing of the manuscript: F. Zhang, H. Sheng, T. Lan

Corresponding author

Correspondence to Feng Zhang.

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Ethics approval

The animal study was reviewed and approved by the Ethics Committee of Animal Experiments of Quzhou People’s Hospital, China.

Conflict of interest

The authors declare no competing interests.

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Highlights

• YEATS2 promotes pancreatic cancer progression.

• YEATS2 regulates NF-κB activity in pancreatic cancer cells.

• YEATS2 modulates TAK1 stability.

• YEATS2 is a transcriptional cofactor for NF-κB-mediated gene expression.

Supplementary Information

Supplemental Fig. 1

Knockdown efficiency of tested shRNA. The expression of shRNAs was delivered by lentiviruses. Cell lysates were collected 2 days after transduction and subjected to western blotting using YEATS2 specific antibody. (PNG 5361 kb)

High Resolution Image (TIF 112 kb)

Supplemental Fig. 2

Overexpression of YEATS2 enhances cell proliferation and colony formation in vitro. Overexpression of YEATS2 in MIA Paca-2 and PANC-1 PDCA cells was mediated by lentiviruses. Cell proliferation was measured by cell counting. Colonies was stained by crystal violet solution. At least 5 fields for each treatment were calculated in size and number. (PNG 13738 kb)

High Resolution Image (TIF 1031 kb)

Supplemental Fig. 3

YEATS2 knockdown affects NF-κB pathway associated gene expression. RNA-seq was performed in MIA cells transduced with scramble (ctrl) or shRNA targeting YEATS2 (shY2). The altered mRNA expression of NF-κB pathway associated genes was shown as heatmap. (PNG 6761 kb)

High Resolution Image (TIF 102 kb)

Supplemental Fig. 4

The correlation of the expression of NF-κB target genes with YEATS2 in human PDAC samples. Eleven NF-κB target genes were analyzed using TCGA database. Among them, the expression of eight genes was significantly correlated with YEATS2 (p<0.01). (PNG 2949 kb)

High Resolution Image (TIF 195 kb)

Supplemental Fig. 5

YEATS2 interacts with p65 in vivo in multiple sites. FLAG-tagged YEATS2 variants with different section deletion were expressed in MIA PaCa2 cells. (A) The schematic diagram of the YEATS2 variants. Flag tags were fused in N-terminal of these variants. (B) Co-IP assay using the beads conjugated with antibody against Flag tag. (PNG 31517 kb)

High Resolution Image (TIF 345 kb)

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Sheng, H., Zheng, F., Lan, T. et al. YEATS2 regulates the activation of TAK1/NF-κB pathway and is critical for pancreatic ductal adenocarcinoma cell survival. Cell Biol Toxicol 39, 1–16 (2023). https://doi.org/10.1007/s10565-021-09671-4

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