Genomic characterization of genes encoding histone acetylation modulator proteins identifies therapeutic targets for cancer treatment

Abstract

A growing emphasis in anticancer drug discovery efforts has been on targeting histone acetylation modulators. Here we comprehensively analyze the genomic alterations of the genes encoding histone acetylation modulator proteins (HAMPs) in the Cancer Genome Atlas cohort and observe that HAMPs have a high frequency of focal copy number alterations and recurrent mutations, whereas transcript fusions of HAMPs are relatively rare genomic events in common adult cancers. Collectively, 86.3% (63/73) of HAMPs have recurrent alterations in at least 1 cancer type and 16 HAMPs, including 9 understudied HAMPs, are identified as putative therapeutic targets across multiple cancer types. For example, the recurrent focal amplification of BRD9 is observed in 9 cancer types and genetic depletion of BRD9 inhibits tumor growth. Our systematic genomic analysis of HAMPs across a large-scale cancer specimen cohort may facilitate the identification and prioritization of potential drug targets and selection of suitable patients for precision treatment.

Metagenomic characterization of lysine acetyltransferases in human cancer and their association with clinicopathologic features

“…For example, KAT6A is recurrently rearranged and fused to that of CREBBP/EP300 and other partner genes in acute myeloid leukemia 15,16 . Recurrent amplification of the KAT6A and KAT6B genes has been identified in various solid tumors, including breast cancer, ovarian cancer, uterine cervix cancer, lung adenocarcinoma, colon and rectal adenocarcinomas, and medulloblastoma 9,15,17. Nuclear receptor coactivators, including NCOA1 and NCOA3, are overexpressed in breast, prostate, endometrial, and pancreatic cancers where they promote tumor growth, invasion, metastasis, and chemoresistance 18 …”

Genome-Wide CRISPR Screening Identifies BRD9 as a Druggable Component of Interferon-Stimulated Gene Expression and Antiviral Activity

“…This finding could have implications for the consideration of BRD9 as a viable therapeutic target in the treatment of some autoinflammatory interferonopathies 9–17 , particularly under specific circumstances where broad targeting of JAK-mediated signaling may not be appropriate 21,22 . Furthermore, we also note that BRD9 inhibition (or degradation) is an attractive therapeutic aim for the treatment of several cancers 24,44,60 . Therefore, our data should also raise awareness that, in such applications, drugs targeting BRD9 may have the undesirable side-effect of limiting the effectiveness of endogenous host innate antiviral IFN responses, thereby potentially increasing the susceptibility of individuals to some infections.…”

Tumor Targeting Strategies of Smart Fluorescent Nanoparticles and Their Applications in Cancer Diagnosis and Treatment

“…Recently, many new tumor therapeutic targets have been discovered through this method with remarkable results. [308,309] Improving the therapeutic effect on cancer, prolonging the life of patients and reducing the toxicity and side effects are the goals that researchers have been pursuing. To this end, scientists have been making continuous efforts.…”