UHRF1 overexpression promotes osteosarcoma metastasis through altered exosome production and AMPK/SEMA3E suppression

Stephanie C Wu; Ahhyun Kim; Yijun Gu; Daniel I Martinez; Loredana Zocchi; Claire C Chen; Jocelyne Lopez; Kelsey Salcido; Sarah Singh; Jie Wu; Ali Nael; Claudia A Benavente

doi:10.1038/s41389-022-00430-6

UHRF1 overexpression promotes osteosarcoma metastasis through altered exosome production and AMPK/SEMA3E suppression

Oncogenesis. 2022 Sep 6;11(1):51. doi: 10.1038/s41389-022-00430-6.

Authors

Stephanie C Wu^{1

2}, Ahhyun Kim¹, Yijun Gu¹, Daniel I Martinez², Loredana Zocchi¹, Claire C Chen¹, Jocelyne Lopez², Kelsey Salcido², Sarah Singh², Jie Wu^{3

4}, Ali Nael^{5

6}, Claudia A Benavente^{7

8

9}

Affiliations

¹ Department of Pharmaceutical Sciences, University of California, Irvine, CA, 92697, USA.
² Department of Developmental and Cell Biology, University of California, Irvine, CA, 92697, USA.
³ Department of Biological Chemistry, University of California, Irvine, CA, 92697, USA.
⁴ Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, 92697, USA.
⁵ Department of Pathology, University of California, Irvine, CA, 92697, USA.
⁶ Department of Pathology, Children's Hospital of Orange County, Orange, CA, 92868, USA.
⁷ Department of Pharmaceutical Sciences, University of California, Irvine, CA, 92697, USA. Claudia.benavente@uci.edu.
⁸ Department of Developmental and Cell Biology, University of California, Irvine, CA, 92697, USA. Claudia.benavente@uci.edu.
⁹ Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, 92697, USA. Claudia.benavente@uci.edu.

Abstract

Loss-of-function mutations at the retinoblastoma (RB1) gene are associated with increased mortality, metastasis, and poor therapeutic outcome in several cancers, including osteosarcoma. However, the mechanism(s) through which RB1 loss worsens clinical outcome remains understudied. Ubiquitin-like with PHD and Ring Finger domains 1 (UHRF1) has been identified as a critical downstream effector of the RB/E2F signaling pathway that is overexpressed in various cancers. Here, we determined the role and regulatory mechanisms of UHRF1 in rendering osteosarcoma cells more aggressive. Higher UHRF1 expression correlated with malignancy in osteosarcoma cell lines, clinical samples, and genetically engineered mouse models. Gain- and loss-of-function assays revealed that UHRF1 has cell-intrinsic and extrinsic functions promoting cell proliferation, migration, invasion, angiogenesis, and metastasis. UHRF1 overexpression induced angiogenesis by suppressing AMPK activation and Semaphorin 3E (SEMA3E) expression. Further, UHRF1-mediated migration and metastasis resulted, at least in part, through altered expression of extracellular vesicles and their cargo, including urokinase-type plasminogen activator (uPA). Novel osteosarcoma genetically engineered mouse models confirmed that knocking out Uhrf1 considerably decreased metastasis and reversed the poorer survival associated with Rb1 loss. This presents a new mechanistic insight into RB1 loss-associated poor prognosis and novel oncogenic roles of UHRF1 in the regulation of angiogenesis and exosome secretion, both critical for osteosarcoma metastasis. This provides substantial support for targeting UHRF1 or its downstream effectors as novel therapeutic options to improve current treatment for osteosarcoma.

Abstract

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