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QSER1 preserves the suppressive status of the pro-apoptotic genes to prevent apoptosis

Abstract

Activation of the pro-apoptotic genes by the p53 family is a critical step in induction of apoptosis. However, the molecular signaling underlying their suppression remains largely unknown. Here, we report a general role of QSER1 in preventing apoptosis. QSER1 is widely up-regulated in multiple cancers, and its up-regulation correlates with poor clinic outcomes. QSER1 knockdown significantly promotes apoptosis in both p53 wild type and mutant cancer cells. Interestingly, we show that QSER1 and p53 occupy distinct cis-regulatory regions in a common subset of the pro-apoptotic genes, and function antagonistically to maintain their proper expression. Furthermore, we identify a key regulatory DNA element named QSER1 binding site in PUMA (QBP). Deletion of QBP de-represses PUMA and induces apoptosis. Mechanistically, QSER1 functions together with SIN3A to suppress PUMA in a p53-dependent and -independent manner, suggesting that QSER1 inhibition might be a potential therapeutic strategy to induce apoptosis in cancers.

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Fig. 1: Elevated QSER1 expression in multiple cancers is associated with poor clinical outcomes.
Fig. 2: QSER1 knockdown inhibits cell growth, and induces apoptosis in cancer cells.
Fig. 3: QSER1 represses p53 target apoptosis genes through binding to these gene loci.
Fig. 4: QSER1 and p53 could function antagonistically through mutual regulation.
Fig. 5: QSER1 represses p53 target pro-apoptotic genes in the absence of p53.
Fig. 6: QSER1 functions through SIN3A in suppressing PUMA expression.
Fig. 7: Working model of QSER1 mediated suppression of the pro-apoptotic genes.

Data availability

The ChIP-seq and RNA-seq data were deposited in the GEO dataset under the accession number GSE180229. This paper does not report original code.

Code availability

The ChIP-seq and RNA-seq data were deposited in the GEO dataset under the accession number GSE180229. This paper does not report original code.

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Acknowledgements

The authors are grateful to the Lin & Luo lab members for helpful discussion of this study. We thank Prof. Min Wu from Wuhan University for providing HCT116 WT and p53 KO cell lines, and Prof. Kai Chen and Mr. Quanyong Zhang from Kunming University of Science and Technology for the technical support.

Funding

Studies in this paper were supported by funds provided by National Key R&D Program of China (2018YFA0800100 to CL), National Natural Science Foundation of China (32030017, 31970617 to CL; 31970626 to ZL), Shenzhen Science and Technology Program (JCYJ20210324133602008 to CL; JCYJ20210324133601005 to ZL), Jiangsu Provincial Key Laboratory of Critical Care Medicine (JSKLCCM-2021–01–004 to ZL), Fundamental Research Funds for the Central Universities and ZhiShan Scholar Program of Southeast University (2242022R40063 to KF).

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KF, CL, and ZL designed the study, and wrote the manuscript with the assistance of the other authors. XZ, KF, RY, FL, YW, M.F., and SH performed the experiments. XZ, KF, XL, MW, YL, JH, CL, and ZL analyzed the data. CG collected and analyzed the clinical data. WH discussed and wrote the manuscript. CL and ZL provided resources, funding, and supervised the work.

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Correspondence to Chengqi Lin or Zhuojuan Luo.

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Zhao, X., Fang, K., Liu, X. et al. QSER1 preserves the suppressive status of the pro-apoptotic genes to prevent apoptosis. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01085-x

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