Identification of histone methyltransferase NSD2 as an important oncogenic gene in colorectal cancer

Li-Hao Zhao,Jing-Jing Lu,Mi-Xue Sun,Xiao-Hua Zhang,Gang Li,Quan Li,Fang Wu,Zhi-Jun Huang

doi:10.1038/s41419-021-04267-6

Abstract

Colorectal cancer (CRC) is the second common cause of cancer-related human mortalities. Dysregulation of histone 3 (H3) methylation could lead to transcriptional activation of multiple oncogenes, which is closely associated with CRC tumorigenesis and progression. Nuclear receptor-binding SET Domain protein 2 (NSD2) is a key histone methyltransferase catalyzing histone H3 lysine 36 dimethylation (H3K36me2). Its expression, the potential functions, and molecular mechanisms in CRC are studied here. Gene Expression Profiling Interactive Analysis (GEPIA) bioinformatics results showed that the NSD2 mRNA expression is elevated in both colon cancers and rectal cancers. Furthermore, NSD2 mRNA and protein expression levels in local colon cancer tissues are significantly higher than those in matched surrounding normal tissues. In primary human colon cancer cells and established CRC cell lines, shRNA-induced silencing or CRISPR/Cas9-induced knockout of NSD2 inhibited cell viability, proliferation, cell cycle progression, migration, and invasion. Furthermore, NSD2 shRNA or knockout induced mitochondrial depolarization, DNA damage, and apoptosis in the primary and established CRC cells. Contrarily, ectopic NSD2 overexpression in primary colon cancer cells further enhanced cell proliferation, migration, and invasion. H3K36me2, expressions of multiple oncogenes (ADAM9, EGFR, Sox2, Bcl-2, SYK, and MET) and Akt activation were significantly decreased after NSD2 silencing or knockout in primary colon cancer cells. Their levels were however increased after ectopic NSD2 overexpression. A catalytic inactive NSD2 (Y1179A) also inhibited H3K36me2, multiple oncogenes expression, and Akt activation, as well as cell proliferation and migration in primary colon cancer cells. In vivo, intratumoral injection of adeno-associated virus (AAV)-packed NSD2 shRNA largely inhibited primary colon cancer cell xenograft growth in nude mice. Together, NSD2 exerted oncogenic functions in CRC and could be a promising therapeutic target.

Highlights

Colorectal cancer (CRC) is the second most common cause of cancer mortalities around the world [1, 2]
Nuclear receptor-binding SET domain protein 2 (NSD2) mRNA upregulation was detected in the rectal cancer tissues (n = 92), whereas relative low expression was detected in normal rectal tissues (n = 318) (Fig. 1A)
When testing NSD2 protein expression using western blotting assays, we found that NSD2 protein was overexpressed in colon cancer tissues in five representative patients (“Patient-1# to Patient-5#,” Fig. 1C)

Summary

Introduction

Colorectal cancer (CRC) is the second most common cause of cancer mortalities around the world [1, 2]. Over 53,000 patients will die from this devastating disease, including about 18,000 cases and 3500 deaths in younger individuals (aged 50 years and under) [3]. The death rate of CRC declined 3% annually in the older individuals (over 65 years), but increased by 1.3% annually in younger CRC patients [3]. It is urgent to further explore the underlying mechanisms responsible for tumorigenesis and progression of CRC [5, 6]. It is the research focus of our group [7, 8]. NSD2 catalyzes histone 3 lysine 36 dimethylation (H3K36me2) [11], required for the transcriptional activation of certain genes (including multiple oncogenes) [12,13,14,15,16,17]

Methods

Results

Discussion

Conclusion