Journal
JOURNAL OF PROTEOME RESEARCH
Volume 20, Issue 9, Pages 4462-4474Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jproteome.1c00437
Keywords
TurboID; indisulam; quantitative proteomics; proliferation; gastric cancer; protein degradation; DCAF15; RBM39
Categories
Funding
- National Key R&D Program of China [2019YFA0802400]
- National Natural Science Foundation of China [32171437]
- Open Project Program of the State Key Laboratory of Proteomics [SKLP-O201905]
- Jiangsu Provincial Bureau of Traditional Chinese Medicine [YB2020070]
- Talent Program in Six Major Disciplines in Jiangsu Province [SWYY-080]
- Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions
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The study confirmed the inhibitory effect of indisulam on the proliferation of gastric cancer cells, showing that it promotes ubiquitination and degradation of RBM39 by enhancing its interaction with DCAF15. This mechanism highlights the potential of indisulam as a treatment for gastric cancer through proteolysis.
Indisulam exhibits antitumor activity against several cancer cells. Although the DCAF15-indisulam-RBM39 axis has been well documented in the inhibition of cancer cell growth, it is unknown whether RBM39 degradation alone is the mechanism of action of indisulam. Here, we verified the inhibitory effect of indisulam on the proliferation of gastric cancer cells and its dependence on DCAF15. Proximity-dependent biotin labeling with TurboID and quantitative proteomics revealed that indisulam indeed promoted the interaction between DCAF15 and RBM39. Immunoblotting and immunofluorescence also revealed that indisulam promoted the ubiquitin-mediated RBM39 degradation and RBM39 colocalized with DCAF15 in the nucleus. DCAF15 knockdown almost completely abolished the indisulam-mediated RBM39 reduction. Further knockdown of RBM39 eliminated the effect of DCAF15 on the proliferation of gastric cancer cells upon indisulam treatment. Immunoblotting of gastric tumor tissues confirmed the downregulation of RBM39 by indisulam. Database analysis unveiled that RBM39 was highly expressed in gastric cancer tissues and its high expression significantly shortened the survival time of gastric cancer patients. Taken together, we demonstrated that indisulam enhanced RBM39 ubiquitination and degradation by promoting its interaction with DCAF15, thus inhibiting the proliferation of gastric cancer cells. This work may provide valuable information for drug discovery through proteolysis targeting chimeras. MS data were deposited in ProteomeXchange (Dataset identifier: PXD024168).
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