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PACT promotes the metastasis of basal-like breast cancer through Rac1 SUMOylation and activation

Oncogene volume 41, pages 4282–4294 (2022)Cite this article

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Abstract

Most basal-like breast cancers (BLBCs) are triple-negative breast cancers (TNBCs), which is associated with high malignancy, high rate of recurrence and distant metastasis, and poor prognosis among all types of breast cancer. However, there are currently no effective therapies for BLBC. Furthermore, chemoresistance limits the therapeutic options for BLBC treatment. In this study, we screen out protein activator of the interferon-induced protein kinase (PACT) as an essential gene in BLBC metastasis. We find that high PACT expression level was associated with poor prognosis among BLBC patients. In vivo and in vitro investigations indicated that PACT could regulate BLBC metastasis by interacting with SUMO-conjugating enzyme Ubc9 to stimulate the SUMOylation and thus consequently the activation of Rac1. BLBC patients receiving chemotherapy presents poorer prognosis with PACT high expression, and PACT disruption sensitizes experimental mammary tumor metastases to chemotherapy, thus providing insights to consider PACT as a potential therapeutic target to overcome acquired chemoresistance in BLBC.

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Fig. 1: PACT is screened as an upregulated protein in a BLBC metastasis model.
Fig. 2: PACT is correlated with poor prognosis and pathogenesis in breast cancer and is highly expressed specifically in BLBC.
Fig. 3: PACT promotes metastasis of BLBC cell.
Fig. 4: PACT activates Rac1 activity.
Fig. 5: PACT directly interacts with Ubc9 and regulates Rac1 SUMOylation.
Fig. 6: Rac1 SUMOylation is necessary for its activation by PACT.
Fig. 7: Inhibition of PACT enhances the therapeutic effect of chemotherapy on BLBC metastasis.

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Data availability

RNA seq and RIP seq data generated for this publication have been deposited in NCBI’s SRA database under the accession: PRJNA643693

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (31701217 to LW, and 31570921 to ZJK), Shanghai Key Laboratory of Health Identification and Assessment (13DZ2261000), Shanghai Municipal Commission of Health and Family Planning (201540206 to ZJK).

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Author notes

  1. These authors contributed equally: Luyao Wei, Wantao Wang, Junxia Yao.

Authors and Affiliations

  1. The Academy of Integrative Medicine, Shanghai Key Laboratory of Health Identification and Assessment, Department of Biochemistry, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, PR China

    Luyao Wei, Wantao Wang, Hanqing Ding, Deheng Wang & Zun-Ji Ke

  2. Department of Pathology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158 Gongyuan Road, Shanghai, 201700, PR China

    Junxia Yao

  3. Department of Internal Medicine of Traditional Chinese Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, PR China

    Zhengyu Cui

  4. Department of Internal Classic of Medicine, School of Basic Medicine Sciences, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, PR China

    Zihang Xu

  5. Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, PR China

    Xiaojun Wu

  6. Department of Pathology, University of Iowa Carver College of Medicine, 51 Newton Road, Iowa City, IA, 52242, USA

    Jia Luo

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Contributions

ZJK and JL oversaw the study. ZJK and LW designed the research, outlined the manuscript, contributed to the literature search. ZJK, DW and XW contribute to manuscript editing. LW, WW, ZC and ZX contribute to data collection, and data analysis, provided the figures. LW drafted the manuscript, helped with data interpretation with additional input from all authors. JY collected clinical sample and did the staining.

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Correspondence to Zun-Ji Ke.

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All animal experiments were carried out with the approval of the institutional Animal Care and Use Committee at Shanghai University of Traditional Chinese Medicine. (Ethics license, PZSHUTCM191108010). The breast cancer specimens used in the current study were obtained from The Zhongshan Hospital of Fudan University, Qingpu branch with patient consent and institutional review board approval.

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Wei, L., Wang, W., Yao, J. et al. PACT promotes the metastasis of basal-like breast cancer through Rac1 SUMOylation and activation. Oncogene 41, 4282–4294 (2022). https://doi.org/10.1038/s41388-022-02431-6

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