PIM3-mediated phosphorylation stabilizes myeloid leukemia factor 2 to promote metastasis in osteosarcoma

Osteosarcoma is the most common primary malignant bone cancer, characterized by a high incidence of lung metastasis and a lack of therapeutic targets. Here, by combining an in vivo CRISPR activation screen with the interactome of STUB1, a tumor suppressor in osteosarcoma, we identified that myeloid leukemia factor 2 (MLF2) promotes osteosarcoma metastasis. Mechanistically, MLF2 disrupted the interaction between BiP and IRE1α, thereby activating the IRE1α/XBP1-S-MMP9 axis. The E3 ligase STUB1 ubiquitinated MLF2 at Lys119 and targeted it for proteasomal degradation, whereas PIM3-mediated phosphorylation of MLF2 at Ser65 enhanced its stabilizing interaction with USP21. Our findings demonstrate that the PIM3/MLF2 axis is a critical regulator of osteosarcoma lung metastasis. We propose PIM3 as a potential therapeutic target for patients with osteosarcoma lung metastasis.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-10-14
DOI
https://doi.org/10.1172/jci191040
Primary Topic
Cancer Mechanisms and Therapy
Type
article
Field-Weighted Citation Impact
0.00

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article

PIM3-mediated phosphorylation stabilizes myeloid leukemia factor 2 to promote metastasis in osteosarcoma

Jun Deng, Xin Wang, Xinhao Yu, Di-an Lin et al.
Journal of Clinical Investigation
Cancer Mechanisms and Therapy
article

PIM3-mediated phosphorylation stabilizes myeloid leukemia factor 2 to promote metastasis in osteosarcoma

Jun Deng, Xin Wang, Xinhao Yu, Di-an Lin, Cuiling Zeng, Weixuan Chen, Shang Wang, J. Lao, Ruhua Zhang, Tiebang Kang, Dan Liao, Jing Zhong, Yu Zhang, Wenqiang Liu, Li Zhong, Qi Zhao
article en

Abstract

Osteosarcoma is the most common primary malignant bone cancer, characterized by a high incidence of lung metastasis and a lack of therapeutic targets. Here, by combining an in vivo CRISPR activation screen with the interactome of STUB1, a tumor suppressor in osteosarcoma, we identified that myeloid leukemia factor 2 (MLF2) promotes osteosarcoma metastasis. Mechanistically, MLF2 disrupted the interaction between BiP and IRE1α, thereby activating the IRE1α/XBP1-S-MMP9 axis. The E3 ligase STUB1 ubiquitinated MLF2 at Lys119 and targeted it for proteasomal degradation, whereas PIM3-mediated phosphorylation of MLF2 at Ser65 enhanced its stabilizing interaction with USP21. Our findings demonstrate that the PIM3/MLF2 axis is a critical regulator of osteosarcoma lung metastasis. We propose PIM3 as a potential therapeutic target for patients with osteosarcoma lung metastasis.

Journal of Clinical InvestigationVol. 135(20)
Sun Yat-sen University (CN), The Seventh Affiliated Hospital of Sun Yat-sen University (CN), Shenzhen Institutes of Advanced Technology (CN), Sun Yat-sen University Cancer Center (CN)
National Natural Science Foundation of China
Openalex Percentile: Top 59%
Cancer Mechanisms and Therapy
DOIOpen Access PDFOpenAlex
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