KAT6B Is a Tumor Suppressor Histone H3 Lysine 23 Acetyltransferase Undergoing Genomic Loss in Small Cell Lung Cancer

Abstract

Recent efforts to sequence human cancer genomes have highlighted that point mutations in genes involved in the epigenetic setting occur in tumor cells. Small cell lung cancer (SCLC) is an aggressive tumor with poor prognosis, where little is known about the genetic events related to its development. Herein, we have identified the presence of homozygous deletions of the candidate histone acetyltransferase KAT6B, and the loss of the corresponding transcript, in SCLC cell lines and primary tumors. Furthermore, we show, in vitro and in vivo, that the depletion of KAT6B expression enhances cancer growth, while its restoration induces tumor suppressor-like features. Most importantly, we demonstrate that KAT6B exerts its tumor-inhibitory role through a newly defined type of histone H3 Lys23 acetyltransferase activity.

Regulation of KAT6 Acetyltransferases and Their Roles in Cell Cycle Progression, Stem Cell Maintenance, and Human Disease

“…Therefore, Enok may have a role in regulating the bulk charges of histones in specific chromatin regions. Consistent with the studies in flies, global H3K23ac levels in human cells depend on the KAT6B MORF, confirming that KAT6 is the major HAT for establishing the H3K23ac mark in higher organisms (44).…”

“…2) (41)(42)(43)(44). While MOZ acetylates H3K14 in vitro and is important for the H3K9ac levels at several target genes, the global levels of H3K9ac and H3K14ac are not affected in the absence of MOZ, indicating that other HATs can compensate for the loss of MOZ-mediated histone acetylation (25,42,45).…”

Targeting p300 Addiction inCBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation ofMYCExpression

“…However, it is possible that mutations in other genes involved in chromatin regulation might also affect this vulnerability, because cancer genomes frequently contain aberrations in a variety of those genes. In fact, a recent study newly identifi ed KAT6B as a gene that is frequently defi cient in lung cancer ( 38 ). Therefore, to obtain a complete picture of vulnerability to depletion of p300 and other HATs, further studies are warranted.…”

“…22 , 32-37 ). In addition, the recent detection in lung cancer of deleterious mutations of KAT6B , which encodes another histone acetyltransferase (HAT), expands the known role of HAT gene aberrations in carcinogenesis ( 38 ). Recurrent missense mutations in CBP tend to cluster around the region encoding the HAT domain.…”

Genome-wide association studies and epigenome-wide association studies go together in cancer control

“…Epigenetic silencing of FOXD3 involved in proliferation, invasion and metastasis [59] Hypermethylation of p15, p16, p21, p27, and RASSF1A [62] Susceptibility locus 1p36.22 [60] SNP rs17401966 in KIF1B on chromosome 1p36.22 that was highly associated with HBV-related HCC [60] Loss of DNA copy number affecting expression of RGS17 and NR2E1 in liver cancer [61] Lung cancer miRNA profiling and HOXA9 promoter methylation as biomarkers of lung cancer recurrence as determined by EWAS [63] Genomic loss of KAT6B coding histone H3 lysine acetyltransferase [66] COPD with lung cancer Sensitive loci at 15q25, 4q31, 4q22, 6q21, and 1q23 [64] In a study with 1400 participants subphenotyped for the presence of COPD and matched for smoking exposure [64] Polymorphism rs7963551 (study conducted in Chinese population) [67] High copy number variation of cancerrelated miRNAs and DICER1 [65] Somatic genomic rearrangements of TP73 resulting its oncogenic activities [68] future science group www.futuremedicine.com a study of GWAS of African-Americans and European Americans [104].…”