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PCDHB14 promotes ferroptosis and is a novel tumor suppressor in hepatocellular carcinoma

Abstract

Liver cancer, a result of multifactorial interplay between heredity and the environment, is one of the leading causes of cancer-related death worldwide. Hepatocellular carcinoma (HCC) is the most common histologic type of primary liver cancer. Here, we reported that deficiency in PCDHB14, a member of the cadherin superfamily, participates in the progression of HCC. We found that PCDHB14 is inactivated by aberrant methylation of its promoter in HCC patients and that PCDHB14 functions as a tumor suppressor to promote cell cycle arrest, inhibit cell proliferation, and induce ferroptosis. Furthermore, PCDHB14 ablation dramatically enhanced diethylenenitrite-induced HCC development. Mechanistically, PCDHB14 is induced by p53, and increased PCDHB14 downregulates the expression of SLC7A11, which is critical for ferroptosis. This effect is mediated by accelerated p65 protein degradation resulting from PCDHB14 promoting E3 ubiquitin ligase RNF182-mediated ubiquitination of p65 to block p65 binding to the promoter of SLC7A11. This study reports the new discovery that PCDHB14 serves as a potential prognostic marker for HCC.

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Fig. 1: PCDHB14 expression is decreased in tumor tissues and associated with prognosis in HCC patients.
Fig. 2: TP53 induces PCDHB14 expression.
Fig. 3: PCDHB14 inhibits malignant progression of liver cancer.
Fig. 4: PCDHB14 downregulation promotes malignant progression of liver cancer.
Fig. 5: PCDHB14 inhibits SLC7A11 expression to promote ferroptosis.
Fig. 6: PCDHB14 enhances RNF182-mediated ubiquitination of p65 by protein-to-protein binding.
Fig. 7: PCDHB14 deletion increases DEN-induced tumorigenesis in mice.

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Acknowledgements

We thank Prof. Yinming Liang for sharing mice. We also thank the contributions of all of Yongguang Tao’s lab members.

Funding

This work is supported by National Natural Science Foundation of China [81872285 (YS), 81874139 and 82073097 (SL), 82072594 (YT), 82073136 (DX)], Natural Science Foundation of Hunan Province [2021JJ30907 (YS)], [2020JJ5790 (CM)], [2021JJ40937 (YLiu)], China Postdoctoral Science Foundation [2021M700173 (YLiu)] and the Hunan Provincial Key Area R&D Program [2021SK2013 (YT)].

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YT, YS, DX, and SL designed/planned the study and wrote the paper. YLiu performed experiments using the three types of cells and analyzed data. YLiu, CM, and NL participated in writing the paper. OY and DX performed imaging analysis. YLiu, YZ, YC, OY, and YLiang performed in vitro biochemical experiments. TL, ZW, DX, LC, YC, and YT participated in the discussion of related experiments. WL, SL, and NL performed computational modeling. XD acquired and analyzed clinical and experimental data. YLiu and OY performed experiments and analyzed data.

Corresponding authors

Correspondence to Ying Shi, Desheng Xiao or Yongguang Tao.

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Liu, Y., Ouyang, L., Mao, C. et al. PCDHB14 promotes ferroptosis and is a novel tumor suppressor in hepatocellular carcinoma. Oncogene 41, 3570–3583 (2022). https://doi.org/10.1038/s41388-022-02370-2

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