Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy

Abstract

Recombinant TRAIL and agonistic antibodies to death receptors (DRs) have been in clinical trial but displayed limited anti-cancer efficacy. Lack of functional DR expression in tumors is a major limiting factor. We report here that chromatin regulator KDM4A/ JMJD2A, not KDM4B, has a pivotal role in silencing tumor cell expression of both TRAIL and its receptor DR5. In TRAIL-sensitive and -resistant cancer cells of lung, breast and prostate, KDM4A small-molecule inhibitor compound-4 (C-4) or gene silencing strongly induces TRAIL and DR5 expression, and causes TRAIL-dependent apoptotic cell death. KDM4A inhibition also strongly sensitizes cells to TRAIL. C-4 alone potently inhibits tumor growth with marked induction of TRAIL and DR5 expression in the treated tumors and effectively sensitizes them to the newly developed TRAIL-inducer ONC201. Mechanistically, C-4 does not appear to act through the Akt-ERK-FOXO3a pathway. Instead, it switches histone modifying enzyme complexes at promoters of TRAIL and DR5 transcriptional activator CHOP gene by dissociating KDM4A and nuclear receptor corepressor (NCoR)-HDAC complex and inducing the recruitment of histone acetylase CBP. Thus, our results reveal KDM4A as a key epigenetic silencer of TRAIL and DR5 in tumors and establish inhibitors of KDM4A as a novel strategy for effectively sensitizing tumors to TRAIL pathway-based therapeutics. 1-5 The binding triggers configurational changes in the receptor trimer and leads to formation of the deathinducing signaling complex (DISC). Depending on cellular context, extrinsic and/or intrinsic pathway of apoptosis is induced with an initial activation of caspase-8 and -10 at DISC and a subsequent activation of the effector caspases such as caspase -3 or -7. The high-tumor cell selectivity and potency in induction of cell death by TRAIL pathway prompted development of therapeutics in the forms of recombinant soluble TRAIL and agonistic TRAIL-R antibodies. 6,7 However, recent clinical trials demonstrated very limited therapeutic benefits. 8,9 Major resistance mechanisms include low expression and/or function of the TRAIL receptors, overexpression of TRAIL decoy receptors (DcRs) and aberrant expression/activation of the anti-apoptotic proteins, such as c-Flip, Bcl-2 family members and IAPs.10,11 Many synthetic or natural agents and cellular pathways have been identified in sensitizing cancer cells to TRAIL.12,13 Given the limited stability and/or bio-distribution of the current TRAIL-based therapies, alternative strategies are being sought to induce tumor cell-endogenous TRAIL expression to block tumor growth. For example, a cell-based screening for TRAIL gene promoter activator identified small-molecule ONC210/TIC10. The subsequent encouraging results of ONC201 from xenograft tumor studies led to its recent entry into clinical efficacy evaluation. 14,15 ONC201 apparently induces TRAIL in cancer cells through inhibition of Akt and ERK kinase signaling and promoting nuclear translocation of Foxo3a. Interestingly, it can also upregulate DR5. ...

Zinc-finger proteins in health and disease

“…Interestingly, many ZNFs contain multiple and different types of zinc-finger domains ( Figure 1b ). For example, two lysine demethylases, Lysine Demethylase 4A (KDM4A), a novel target for antitumor therapy, 17 and KDM2A, which is required for DNA damage response, 18 exhibit different zinc-finger compositions. Nevertheless, an important acetyltransferase, Lysine Acetyltransferase 6A (KAT6A), which regulates cell cycle progression, 19 has the same zinc-finger pattern as KDM4A but exhibits a different molecular function.…”

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

“…The chromatin regulator KDM4A acts to silence expression of TRAIL and DR5 by tumor cells [96] . Inhibition of KDM4A/B with the small molecule C-4 induced strong upregulation of TRAIL and DR5 in prostate, lung and breast cancer cells through KDM4A silencing, as well as upregulation of CHOP gene expression.…”

Identification of the histone lysine demethylase KDM4A/JMJD2A as a novel epigenetic target in M1 macrophage polarization induced by oxidized LDL

“…KDM4A is involved in regulation of apoptosis in tumor cells [ 35 , 61 ]. In the present study, we observed that the pan-selective JMJD inhibitor JIB-04 induced robust apoptosis of macrophages, implying a functional role of the JMJD family in macrophage survival.…”