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NSD2 promotes cell durotaxis and drives the transition from polycystic kidney disease to tubulocystic renal cell carcinoma through integrin/FAK/AKT signaling

Oncogene volume 44, pages 3437–3448 (2025)Cite this article

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Abstract

Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system. NSD2 is an H3K36-specific di-methyltransferase that has been reported to participate in diverse biological processes and human tumors. However, its role in RCC remains unclear. Here, we found that NSD2 is highly expressed in RCC, which is associated with poor survival in RCC patients. NSD2 facilitates the transition from Myc-induced polycystic kidney disease to tubulocystic renal cell carcinoma (TCRCC), which is a rare RCC subtype with distinctive clinicopathologic and genetic characterizations. The mice with kidney-specific overexpression of MYC and NSD2 (KMN) display severe cyst burden at only 6 weeks of age, and develop into TCRCC at 12 weeks of age. Mechanistically, NSD2 transcriptionally upregulates the expressions of integrins (Itga4 and Itga11), to further activate the FAK/AKT pathway. In addition, we found that NSD2 enhances cell proliferation on the stiff matrix of PEGDA hydrogel. Moreover, inhibition of FAK signaling relieves the symptoms of KMN mice, and significantly rescues the enhanced cell proliferation caused by NSD2 overexpression in vitro. Together, our findings highlight an epigenetic mechanism by which NSD2 regulates TCRCC tumorigenesis through the integrin/FAK/AKT pathway. This study may also pave the way for the development of targeted, patient-tailored therapies for TCRCC patients with NSD2 amplification or high expression.

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Fig. 1: NSD2 expression increases in RCC patients and is associated with poor RCC prognosis.
Fig. 2: NSD2 promotes the transition from Myc-induced PKD to TCRCC.
Fig. 3: NSD2 activates the ECM-receptor interaction and FAK/AKT pathway.
Fig. 4: NSD2-mediated H3K36me2 facilitates the expression of integrins.
Fig. 5: NSD2 enhances the cell proliferation on the stiff matrix.
Fig. 6: Inhibition of the integrin/FAK/AKT signaling alleviates the tumorigenesis of TCRCC.
Fig. 7: NSD2 promotes the transition from PKD to TCRCC through activating the integrin/FAK/AKT signaling.

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Data availability

The sequencing data sets have been deposited in the National Center for Biotechnology Information (NCBI)’s Gene Expression Omnibus (GEO). RNA-Seq raw data have been deposited in GEO under accession number: GSE266614. CUT-Tag raw data have been deposited in GEO under accession number: GSE264634.

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Acknowledgements

This work was supported by funds from National Key R&D Program of China (2022YFA1302704 to LL and W-QG), National Natural Science Foundation of China (82372604, 82073104 to LL, U23A20441 to W-QG), Science and Technology Commission of Shanghai Municipality (21JC1404100 to W-QG) and 111 project (no. B21024). We thank Genefund Biotech (Shanghai, China) for assistance in the data analysis.

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  1. These authors contributed equally: Wenxin Feng, Ningyuan Liu.

Authors and Affiliations

  1. State Key Laboratory of Systems Medicine for Cancer, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

    Wenxin Feng, Ningyuan Liu, Changwei Liu, Hanyu Rao, Zhuo Chen, Wei Zhang, Yue Xu, Rebiguli Aji, Ziyi Wang, Wei-Qiang Gao & Li Li

  2. School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China

    Wenxin Feng, Ningyuan Liu, Changwei Liu, Hanyu Rao, Zhuo Chen, Wei Zhang, Yue Xu, Rebiguli Aji, Ziyi Wang, Wei-Qiang Gao & Li Li

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Contributions

LL designed experiment and interpreted data; WF and NL. performed most of the experiments; CL, HR, ZC, WZ, YX, RA. and ZW assisted in some experiments; W-QG assisted in some discussion; WF, NL and LL wrote the manuscript; LL provided the overall guidance.

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Correspondence to Li Li.

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Feng, W., Liu, N., Liu, C. et al. NSD2 promotes cell durotaxis and drives the transition from polycystic kidney disease to tubulocystic renal cell carcinoma through integrin/FAK/AKT signaling. Oncogene 44, 3437–3448 (2025). https://doi.org/10.1038/s41388-025-03505-x

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