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bioRxiv · 10.1101/2024.10.03.616541

A feedforward loop between STAT1 and YAP1 stimulates lipid biosynthesis, accelerates tumor growth, and promotes chemotherapy resistance in mutant KRAS colorectal cancer.

Wang, S.·Diao, S.·Kim, H.·Zou, J. Y.·Li, K. K.·Koromilas, A. E.
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Abstract

In tumorous conditions, the transcription factor STAT1, traditionally recognized for its anti-tumor role in immunology, exhibits pro-survival characteristics, though the underlying mechanisms remain unclear. Investigating STAT1s function in isogenic colorectal tumor cells with wild-type or mutant KRAS, we found that STAT1 specifically promotes the survival and proliferation of cells with mutant KRAS. Through gene expression profiling, we discovered a previously unknown role of STAT1 in upregulating sterol and lipid biosynthetic genes specifically in mutant KRAS cells. This effect is driven by STAT1s phosphorylation at serine 727 and its cooperation with STAT3 and STAT5 for the transcriptional upregulation of sterol regulatory element-binding proteins (SREBP) 1 and 2, which boost de novo sterol and lipid biosynthesis. In mutant KRAS cells, STAT1 amplifies the mevalonate pathway, maintaining its serine 727 phosphorylation through RHO GTPase signaling and establishing a positive feedback loop through the transcription factors YAP1 and TEAD4, further driving lipid biosynthesis and tumor growth. Through xenograft tumor assays in mice, we discovered that the STAT1-YAP1 axis plays a role in mutant KRAS tumor cells resistance to mevalonate pathway inhibitors, which can be overcome by pharmacologically targeting the YAP1-TEAD interaction. Additionally, the STAT1-YAP1 arm is essential for the intrinsic resistance to EGFR-targeting therapy in the mutant KRAS colon cancer cells. These findings indicate that the STAT1-YAP1 pathway plays a significant role in therapy resistance and presents a potential therapeutic target in mutant KRAS colorectal cancer.

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Wang, S., Diao, S., Kim, H., Zou, J. Y., Li, K. K., Koromilas, A. E.. 2024-10-04. A feedforward loop between STAT1 and YAP1 stimulates lipid biosynthesis, accelerates tumor growth, and promotes chemotherapy resistance in mutant KRAS colorectal cancer.. https://doi.org/10.1101/2024.10.03.616541

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