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

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.