Kdm1a promotes SCLC progression by transcriptionally silencing the tumor suppressor Rest.

Small cell lung carcinoma (SCLC) is one of the deadliest cancer types, with a 5-year survival rate less than 10%. Kdm1a/Lsd1 has recently been implicated as a potential therapeutic target for SCLC. However, the underlying molecular mechanism by which Kdm1a promotes the oncogenesis of SCLC has not been fully understood. Kdm1a is significantly elevated in most human SCLC specimens, whereas Rest, a tumor suppressor and neuronal repressive transcriptional factor, is typically inactivated. Knock-out of Kdm1a (Kdm1a-KO) in mouse SCLC cell lines resulted in the suppression of cell growth and soft agar colony formation. RNA-Seq analysis of the Kdm1a-KO cells revealed significant repression of a program of neuroendocrine signature genes, and conversely, a significant upregulation of a network of genes capable of inhibiting tumor cell growth. Rest was identified among the top 10 upregulated genes in Kdm1a-KO cells. The treatment of the SCLC cells with Kdm1a demethylase inhibitors resulted in a dramatic up-regulation of Rest similar to the extent of that in Kdm1a-KO cells. Importantly, accompanying the restored expression of the SCLC signature genes, knock-out of Rest in Kdm1a-KO cells rescued the restricted cell growth and soft agar colony formation. Taken together, these novel findings show that Kdm1a is a key transcriptional repressor of Rest, and that suppression of SCLC progression by the targeted inhibition of Kdm1a depends on the reactivation of Rest, suggesting a new strategy for effective SCLC treatment by targeting the Kdm1a/Rest molecular pathway.

The fusiform gyrus exhibits an epigenetic signature for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, and patients with advanced AD frequently lose the ability to identify family members. The fusiform gyrus (FUS) of the brain is critical in facial recognition. However, AD etiology in the FUS of AD patients is poorly understood. New analytical strategies are needed to reveal the genetic and epigenetic basis of AD in FUS. RESULTS: A complex of new analytical paradigms that integrates an array of transcriptomes and methylomes of normal controls, AD patients, and "AD-in-dish" models were used to identify genetic and epigenetic signatures of AD in FUS. Here we identified changes in gene expression that are specific to the FUS in brains of AD patients. These changes are closely linked to key genes in the AD network. Profiling of the methylome (5mC/5hmC/5fC/5caC) at base resolution identified 5 signature genes (COL2A1, CAPN3, COL14A1, STAT5A, SPOCK3) that exhibit perturbed expression, specifically in the FUS and display altered DNA methylome profiles that are common across AD-associated brain regions. Moreover, we demonstrate proof-of-principle that AD-associated methylome changes in these genes effectively predict the disease prognosis with enhanced sensitivity compared to presently used clinical criteria. CONCLUSIONS: This study identified a set of previously unexplored FUS-specific AD genes and their epigenetic characteristics, which may provide new insights into the molecular pathology of AD, attributing the genetic and epigenetic basis of FUS to AD development.