Sheng, Haoyue

Significance The multiple-domain protein ZMYND8 is well known as a chromatin reader that recognizes methylated, acetylated, and/or mutated histones. Here we report that ZMYND8 is overexpressed in human ccRCC, and that it preferentially binds T487-phosphorylated EZH2. We show that in hypoxia-stimulated or von Hippel–Lindau–deficient cells, ZMYND8 binding of EZH2 is important for maintenance of EZH2 phosphorylation level, inhibition of PRC2 complex formation, and enhanced interaction between EZH2 and FOXM1. Our results reveal a reader function of ZMYND8 in recognizing a phosphorylation “code” on a nonhistone protein. Our findings also identify ZMYND8 binding as a facet of regulation and function of EZH2 phosphorylation in the Polycomb-dependent to -independent switch of EZH2/PRC2 activities.

Increasing evidence demonstrated that noncoding RNA is abnormally expressed in cancer tissues and serves a vital role in tumorigenesis, tumor development, and metastasis. The aim of the present study was to determine an lncRNA signature in order to predict the overall survival (OS) of patients with muscle-invasive bladder cancer (MIBC). A total of 246 patients with pathologically confirmed MIBC in The Cancer Genome Atlas (TCGA) dataset were recruited and included in the present study. We choose patients who have smoked less (including never smoking) or more than 15 years. A total of 44 differentially expressed lncRNAs were identified with a fold change larger than 1.5 and a P value < 0.05 through the limma package. Subsequently, a comparison between patients with no tobacco smoke exposure for <15 years and patients who had been exposed to tobacco smoke for >15 years was performed by using the matchIt package. Among the 44 differentially expressed lncRNAs, 5 lncRNAs were identified to be significantly associated with OS. Based on the characteristic risk scores of these 5 lncRNAs, patients were divided into low-risk and high-risk groups and exhibited significant differences in OS. Multivariate Cox regression analysis demonstrated that the 5-lncRNA signature was independent of age, tumor-node metastasis (TNM) staging, lymphatic node status, and adjuvant postoperative radiotherapy. In the present study, a novel 5-lncRNA signature was developed and was demonstrated to be useful in predicting the survival of patients with MIBC. If validated, this lncRNA signature may assist in the selection of a high-risk subpopulation that requires more aggressive therapeutic intervention. The risk scores involved in several associated pathways were identified using gene set enrichment analysis (GSEA). However, the clinical implications and mechanism of these 5 lncRNAs require further investigation.

Abstract The tumor-suppressor protein RB acts as a transcription repressor via interaction of its pocket domain with an LXCXE motif in histone deacetylase (HDAC) proteins such as HDAC1. Here, we demonstrate that HDAC5 deficient for the LXCXE motif interacts with both RB-N (via an FXXXV motif) and RB-C segments, and such interactions are diminished by phosphorylation of RB serine-249/threonine-252 and threonine-821. HDAC5 was frequently downregulated or deleted in human cancers such as prostate cancer. Loss of HDAC5 increased histone H3 lysine 27 acetylation (H3K27-ac) and circumvented RB-mediated repression of cell-cycle–related pro-oncogenic genes. HDAC5 loss also conferred resistance to CDK4/6 inhibitors such as palbociclib in prostate and breast cancer cells in vitro and prostate tumors in vivo, but this effect was overcome by the BET-CBP/p300 dual inhibitor NEO2734. Our findings reveal an unknown role of HDAC5 in RB-mediated histone deacetylation and gene repression and define a new mechanism modulating CDK4/6 inhibitor therapeutic sensitivity in cancer cells. Significance: This study defines a previously uncharacterized role of HDAC5 in tumor suppression and provides a viable strategy to overcome CDK4/6 inhibitor resistance in HDAC5-deficent cancer.