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MRPL33 and its splicing regulator hnRNPK are required for mitochondria function and implicated in tumor progression

Oncogene volume 37, pages 86–94 (2018)Cite this article

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Abstract

MRPL33 gene encodes a large mitoribosomal subunit protein, which may be involved in mitochondrial translation. Although two splice variants of MRPL33 have been described, its splicing regulation remains elusive. Here we observed that inclusion of alternative exon 3 was greatly promoted in a panel of human cancer cells. Depletion of the exon 3-containing long isoform of MRPL33 (MRPL33-L) led to impaired proliferation and increased apoptosis in cancer cell lines and in a xenograft model. MRPL33-L knockdown could also induce mitochondrial dysfunction including increased accumulation of reactive oxygen species, decreased ATP production and 16 S rRNA levels. We further showed that alternative splicing of MRPL33-L pre-mRNA is regulated by hnRNPK and that knocking down hnRNPK could phenocopy MRPL33-L depletion. More importantly, overexpression of MRPL33-L could increase tumorigenic potential of hnRNPK-depleted cancer cells, likely indicating that hnRNPK mediates tumorigenesis through splicing regulation of MRPL33 pre-mRNA. Finally, we found that inclusion of MRPL33 exon 3 was promoted in human colorectal cancer tissues and this was correlated with hnRNPK levels. In summary, our findings underscore the biological significance of MRPL33-L and hnRNPK in the tumor formation and identifies hnRNPK as a critical splicing regulator of MRPL33 pre-mRNA in cancer cells.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation 31570818 to Y Feng and 31370786 to Y Feng and 31601170 to N Wei and 31400677 to W Wu and 81372197 to G Wu and also from the ‘Personalized Medicine-Molecular Signature-based Drug Discovery and Development’, Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12010100).

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Author notes

  1. L Liu, C Luo and Y Luo: These authors contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China

    L Liu, C Luo, Y Luo, L Chen, Y Liu, Y Wang, Y Zhang, N Wei, Z Xie & Y Feng

  2. Department of Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China

    J Han & G Wu

  3. The Nurturing Station for the State Key Laboratory of Subtropical Silviculture, Zhejiang Agriculture and Forestry University, Lin’an, China

    W Wu

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  1. L Liu
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Correspondence to G Wu or Y Feng.

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Liu, L., Luo, C., Luo, Y. et al. MRPL33 and its splicing regulator hnRNPK are required for mitochondria function and implicated in tumor progression. Oncogene 37, 86–94 (2018). https://doi.org/10.1038/onc.2017.314

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