Jumonji histone demethylases are therapeutic targets in small cell lung cancer.

Small cell lung cancer (SCLC) is a recalcitrant cancer of neuroendocrine (NE) origin. Changes in therapeutic approaches against SCLC have been lacking over the decades. Here, we use preclinical models to identify a new therapeutic vulnerability in SCLC consisting of the targetable Jumonji lysine demethylase (KDM) family. We show that Jumonji demethylase inhibitors block malignant growth and that etoposide-resistant SCLC cell lines are particularly sensitive to Jumonji inhibition. Mechanistically, small molecule-mediated inhibition of Jumonji KDMs activates endoplasmic reticulum (ER) stress genes, upregulates ER stress signaling, and triggers apoptotic cell death. Furthermore, Jumonji inhibitors decrease protein levels of SCLC NE markers INSM1 and Secretogranin-3 and of driver transcription factors ASCL1 and NEUROD1. Genetic knockdown of KDM4A, a Jumonji demethylase highly expressed in SCLC and a known regulator of ER stress genes, induces ER stress response genes, decreases INSM1, Secretogranin-3, and NEUROD1 and inhibits proliferation of SCLC in vitro and in vivo. Lastly, we demonstrate that two different small molecule Jumonji KDM inhibitors (pan-inhibitor JIB-04 and KDM4 inhibitor SD70) block the growth of SCLC tumor xenografts in vivo. Our study highlights the translational potential of Jumonji KDM inhibitors against SCLC, a clinically feasible approach in light of recently opened clinical trials evaluating this drug class, and establishes KDM4A as a relevant target across SCLC subtypes.

SIRTifying intestinal nucleotide metabolism.

The intestine is a proliferative tissue subjected to a variety of stresses that disturb its homeostasis. A recent study by Tucker et al. demonstrated that loss of the tumor suppressor SIRT4 leads to increased cell proliferation via the de novo nucleotide biosynthesis pathway over the salvage pathway after ionizing irradiation (IR).

A Novel Pyrazole Exhibits Potent Anticancer Cytotoxicity via Apoptosis, Cell Cycle Arrest, and the Inhibition of Tubulin Polymerization in Triple-Negative Breast Cancer Cells.

In this study, we screened a chemical library to find potent anticancer compounds that are less cytotoxic to non-cancerous cells. This study revealed that pyrazole PTA-1 is a potent anticancer compound. Additionally, we sought to elucidate its mechanism of action (MOA) in triple-negative breast cancer cells. Cytotoxicity was analyzed with the differential nuclear staining assay (DNS). Additional secondary assays were performed to determine the MOA of the compound. The potential MOA of PTA-1 was assessed using whole RNA sequencing, Connectivity Map (CMap) analysis, in silico docking, confocal microscopy, and biochemical assays. PTA-1 is cytotoxic at a low micromolar range in 17 human cancer cell lines, demonstrating less cytotoxicity to non-cancerous human cells, indicating a favorable selective cytotoxicity index (SCI) for the killing of cancer cells. PTA-1 induced phosphatidylserine externalization, caspase-3/7 activation, and DNA fragmentation in triple-negative breast MDA-MB-231 cells, indicating that it induces apoptosis. Additionally, PTA-1 arrests cells in the S and G2/M phases. Furthermore, gene expression analysis revealed that PTA-1 altered the expression of 730 genes at 24 h (198 upregulated and 532 downregulated). A comparison of these gene signatures with those within CMap indicated a profile similar to that of tubulin inhibitors. Subsequent studies revealed that PTA-1 disrupts microtubule organization and inhibits tubulin polymerization. Our results suggest that PTA-1 is a potent drug with cytotoxicity to various cancer cells, induces apoptosis and cell cycle arrest, and inhibits tubulin polymerization, indicating that PTA-1 is an attractive drug for future clinical cancer treatment.