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TP53 mutations upregulate RCP expression via Sp1/3 to drive lung cancer progression

Oncogene volume 41, pages 2357–2371 (2022)Cite this article

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Abstract

Mutant p53 (mtp53) can exert cancer-promoting activities via “gain-of-function”, which has become a popular research target. Although lots of researchers focus on the tumor-suppressor role for p53, the regulation of mutant p53 remains unknown. Here, we report a mechanism by which mtp53 regulate the transcription of Rab coupling protein (RCP) to influence lung cancer behavior. First, we show that RCP is specifically expressed at high levels in lung cancer tissues and cells, and RCP knockout suppresses tumor growth and metastasis. Further mass spectrometry and functional analysis identify that Sp1, Sp3 and Stat3 are the transcriptional activators of RCP. Moreover, p53 is involved in modulating RCP expression in an Sp1/3 dependent manner. Mechanistically, in contrast to wild-type p53 suppression of RCP transcription by decreasing Sp1/3 proteins, TP53 mutations have changed on Sp1/3 expression via “loss-of-function”. Surprisingly, the DNA contact mutants of p53 further robustly enhance their binding ability with Sp1/3 to drive RCP expression through the “gain-of-function” activity. Collectively, we reveal a mechanism by which p53 regulating the transcription of RCP to influence lung cancer progression, which provides new insights for treating p53 mutant lung cancer.

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Fig. 1: RCP is highly expressed in human lung cancer.
Fig. 2: RCP Drives Lung Cancer Cell Proliferation and Invasion in vitro.
Fig. 3: RCP drives lung cancer tumor growth and metastasis in vivo.
Fig. 4: Sp1, Sp3 and Stat3 are identified as transcriptional activators of RAB11FIP1.
Fig. 5: Sp1, Sp3 and Stat3 regulate RAB11FIP1 to increase tumor invasion.
Fig. 6: Wild-type p53 Suppressed RCP Transcription in an Sp1 and Sp3 Dependent Manner.
Fig. 7: Mutant p53 GOF regulate RCP expression dependent on Sp1/3.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82103071 to CW) and the National Major Scientific and Technological Special Project for “Significant New Drugs Development” (No. 20181821569 to YL).

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Author notes

  1. These authors contributed equally: Caihong Wang, Shaosen Zhang.

Authors and Affiliations

  1. Beijing Institute of Tropical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China

    Caihong Wang

  2. School of Life Sciences, Tsinghua University, Beijing, 100084, China

    Caihong Wang, Shaosen Zhang, Boyuan Ma, Yan Fu & Yongzhang Luo

  3. The National Engineering Research Center for Protein Technology, Tsinghua University, Beijing, 100084, China

    Caihong Wang, Shaosen Zhang, Boyuan Ma, Yan Fu & Yongzhang Luo

  4. Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing, 100084, China

    Caihong Wang, Shaosen Zhang, Boyuan Ma, Yan Fu & Yongzhang Luo

  5. Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Shaosen Zhang

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CW and SZ performed all experiments with the assistance from BM and YF. SZ and CW conceived and designed the research. YL supervised the research. C.W and SZ wrote and edited the paper. All authors commented on the paper.

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Correspondence to Yongzhang Luo.

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Wang, C., Zhang, S., Ma, B. et al. TP53 mutations upregulate RCP expression via Sp1/3 to drive lung cancer progression. Oncogene 41, 2357–2371 (2022). https://doi.org/10.1038/s41388-022-02260-7

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