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bioRxiv · 10.1101/2025.09.02.673805

Survivin as a Multifaceted Oncogenic Driver and Therapeutic Target in Renal Cell Carcinoma

Tuli, S.·Inserra, G.·Murakami, Y.·Bae, Y.·Gau, D.
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Abstract

Renal cell carcinoma (RCC) is a heterogeneous malignancy in which clear cell RCC (ccRCC) represents the most aggressive subtype. Survivin (BIRC5), an inhibitor of apoptosis and key regulator of mitosis, is frequently overexpressed in RCC and associated with poor prognosis, yet its broader role in kidney cancer biology remains poorly defined. Here, we analyzed transcriptomic data from the TCGA-KIRC cohort and found that advanced-stage ccRCC exhibits widespread dysregulation of cell cycle pathways, with 1,484 genes upregulated and 479 genes downregulated in stage IV compared to stage I tumors. To define survivins functional contribution, we performed loss-of-function and pharmacologic inhibition studies in RENCA cells. Survivin knockdown or treatment with the small molecule inhibitor YM155 significantly reduced proliferation, S-phase entry, and Cyclin D1 expression, while also impairing both collective and single-cell migration. Beyond cell cycle control, survivin depletion induced notable changes in mitochondrial morphology and bioenergetics, including increased mitochondrial content coupled with reduced oxygen consumption, suggesting accumulation of dysfunctional mitochondria due to impaired clearance. Collectively, these findings identify survivin as a multifaceted oncogenic driver in RCC that integrates cell cycle progression, cytoskeletal organization, and mitochondrial homeostasis. By revealing survivins dual roles in proliferative and metabolic adaptation, this work highlights survivin as both a prognostic biomarker and a therapeutic vulnerability, supporting future strategies that combine survivin inhibition with metabolic or cell cycle-directed therapies for advanced kidney cancer.

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Tuli, S., Inserra, G., Murakami, Y., Bae, Y., Gau, D.. 2025-09-07. Survivin as a Multifaceted Oncogenic Driver and Therapeutic Target in Renal Cell Carcinoma. https://doi.org/10.1101/2025.09.02.673805

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