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CTSL2 is a pro-apoptotic target of E2F1 and a modulator of histone deacetylase inhibitor and DNA damage-induced apoptosis

Oncogene volume 33, pages 1249–1257 (2014)Cite this article

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Abstract

Aberrant regulation of the pRB/E2F1 pathway has been invariably linked to inappropriate proliferation and/apoptosis in human cancers. Therefore, understanding the intricacies of the signaling pathway and identification of novel E2F1 targets involved in apoptosis could pave way for new therapeutic manipulation. Here, we identified CTSL2 (cathepsin L2/cathepsin V) as a novel E2F1 target that participates in E2F1-dependent apoptosis. We showed that E2F1 directly binds to CTSL2 promoter and that CTSL2 is regulated by both exogenous and endogenous E2F1. RNAi-mediated depletion of CTSL2 effectively abrogated ectopic E2F1-induced apoptosis, coupled with reduced lysosomal membrane permeabilization (LMP) and mitochondrial membrane depolarization. CTSL2 knockdown also inhibited apoptosis mediated by the endogenous E2F1 activated by DNA damage. Furthermore, we showed that CTSL2 depletion in cancer cells resulted in inhibition of histone deacetylase inhibitor (HDACi)-induced apoptosis, and conversely ectopic overexpression of CTSL2-sensitized cancer cells to HDACi. This study uncovered a novel E2F1 target implicated in LMP and apoptosis activation, as well as in the modulation of HDACi and chemotherapeutic drugs response.

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Acknowledgements

We thank Dr Kristian Helin for the ER-E2F1 plasmids, Dr Joseph Nevins for the adenoviral E2F1, Dr Andrew Turnell for adenoviral E1A and Dr Claudio Brancolini for IMR90-E1A cells. We are grateful to Li Juntao for providing assistance in data analysis. This work was supported by the Agency for Science, Technology and Research for Singapore.

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Author notes

  1. C H Wong and Z Wu: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Biology and Pharmacology, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore

    C H Wong & Q Yu

  2. State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, PRC

    Z Wu

  3. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Q Yu

  4. Cancer and Stem Cell Biology, DUKE-NUS Graduate Medical School of Singapore, Singapore, Singapore

    Q Yu

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  1. C H Wong
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Correspondence to Q Yu.

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Wong, C., Wu, Z. & Yu, Q. CTSL2 is a pro-apoptotic target of E2F1 and a modulator of histone deacetylase inhibitor and DNA damage-induced apoptosis. Oncogene 33, 1249–1257 (2014). https://doi.org/10.1038/onc.2013.72

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