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PSMD12 interacts with CDKN3 and facilitates pancreatic cancer progression

Cancer Gene Therapy volume 30, pages 1072–1083 (2023)Cite this article

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Abstract

Proteasome 26S subunit, non-ATPase 12 (PSMD12) genes have been implicated in several types of malignancies but the role of PSMD12 in pancreatic cancer (PC) remains elusive. Bioinformatics analysis showed that PSMD12 was highly expressed in PC patients and was associated with shorter overall survival. PSMD12 was also shown to be highly expressed in PC tissues and cell lines. Upregulated PSMD12 showed enhanced cell viability, increased colony formation rate and upregulated levels of PCNA and c-Myc, while the inhibition of PSMD12 abated these levels. PSMD12 knockdown promoted cell apoptosis. The results of xenografts in nude mice confirmed that PSMD12 promoted PC tumor growth in vivo. Protein‒protein interaction network and functional enrichment analyses implied that PSMD12 may have a connection with cyclin-dependent kinase inhibitor 3 (CDKN3). Co‑immunoprecipitation and western blot results confirmed that PSMD12 could interact with and abate the ubiquitination level of CDKN3, thus stabilizing the CDKN3 protein. Rescue assays showed that PSMD12 overexpression caused cell proliferation and that knockdown-induced cell apoptosis could be reversed by CDKN3 regulation. This work reveals the essential roles of PSMD12 in the proliferation and apoptosis of PC development. PSMD12 may regulate CDKN3 expression by interacting with and abating the ubiquitination level of CDKN3, thereby participating in the malignant behavior of PC.

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Fig. 1: PSMD12 is upregulated in pancreatic cancer (PC) tissues and cells.
Fig. 2: PSMD12 enhances PC cell proliferation.
Fig. 3: PSMD12 suppresses PC cell apoptosis.
Fig. 4: PSMD12 promotes PC progression in vivo.
Fig. 5: Protein‒protein interaction networks and functional enrichment analyses of PSMD12 and CDKN3.
Fig. 6: PSMD12 interacts with CDKN3.
Fig. 7: CDKN3 is involved in PSMD12-mediated malignant phenotype of PC.

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Data availability

The data that support the findings of this study are available on request from the corresponding author [XM].

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Authors and Affiliations

  1. Department of Gastroenterology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China

    Jia Ma

  2. Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China

    Wenyang Zhou

  3. Pancreatic Endocrinology Ward, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China

    Yifeng Yuan, Baosheng Wang & Xiangpeng Meng

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Contributions

JM designed the study and contributed to drafting the manuscript. WZ, YY and BW collated the data, carried out data analyses, and produced the initial draft of the manuscript. XM contributed to revising the manuscript. All authors have read and approved the final submitted manuscript.

Corresponding author

Correspondence to Xiangpeng Meng.

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The authors declare no competing interests.

Ethics approval and consent to participate

All animal experiments were approved by the Institutional Animal Care and Use Committee of Shengjing Hospital of China Medical University (code: 2022PS918K). All patients involved in this study were aware and provided informed consent. This study was approved by the Ethics Committee of the Shengjing Hospital of China Medical University (code: 2022PS919K) and performed in accordance with the Declaration of Helsinki.

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Ma, J., Zhou, W., Yuan, Y. et al. PSMD12 interacts with CDKN3 and facilitates pancreatic cancer progression. Cancer Gene Ther 30, 1072–1083 (2023). https://doi.org/10.1038/s41417-023-00609-y

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