The histone methyltransferase Wolf–Hirschhorn syndrome candidate 1‐like 1 (WHSC1L1) is involved in human carcinogenesis

Abstract

Histone lysine methylation plays a fundamental role in chromatin organization. Although a set of histone methyltransferases have been identified and biochemically characterized, the pathological roles of their dysfunction in human cancers are still not well understood. In this study, we demonstrate important roles of WHSC1L1 in human carcinogenesis. Expression levels of WHSC1L1 transcript were significantly elevated in various human cancers including bladder carcinoma. Immunohistochemical analysis of bladder, lung, and liver cancers confirmed overexpression of WHSC1L1. WHSC1L1-specific small interfering RNAs significantly knocked down its expression and resulted in suppression of proliferation of bladder and lung cancer cell lines. WHSC1L1 knockdown induced cell cycle arrest at the G(2)/M phase followed by multinucleation of cancer cells. Expression profile analysis using Affymetrix GeneChip(®) showed that WHSC1L1 affected the expression of a number of genes including CCNG1 and NEK7, which are known to play crucial roles in the cell cycle progression at mitosis. As WHSC1L1 expression is significantly low in various normal tissues including vital organs, WHSC1L1 could be a good candidate molecule for development of novel treatment for various types of cancer.

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

“…NSD3 undergoes copy number amplification in 21% of lung squamous cell carcinomas and 15% of breast invasive carcinomas, with a high correlation between copy number and mRNA expression, suggesting that NSD3 may function as an oncogenic driver [70]. Indeed, RNAi knockdown of NSD3 in non-small-cell lung cancer, colorectal cancer, bladder cancer and breast cancer cell lines with NSD3 overexpression causes reduced cell proliferation due to increased apoptosis or cell cycle arrest in the various cancer cell lines [70,75,76]. The breast epithelial cell line MCF10A is normally highly dependent on growth factors and forms small acinar-like structures in 3D Matrigel culture, but these cells can be transformed by expression of NSD3, which confers growth factor-independent proliferation, colony-forming ability in soft agar and expanded and disorganized growth in 3D culture [76].…”

WHSC1 Promotes Oncogenesis through Regulation of NIMA-Related Kinase-7 in Squamous Cell Carcinoma of the Head and Neck

“…Purified total RNA isolated from these samples was labeled and hybridized onto Affymetrix GeneChip U133 Plus 2.0 oligonucleotide arrays (Affymetrix) according to the manufacturer's instructions (32)(33)(34). Probe signal intensities were normalized by RMA and Quantile normalization methods (using R and Bioconductor).…”

In vitro histone lysine methylation by NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L

“…Increased NSD2 activity is also reported during tumor proliferation in glioblastoma and myeloma [34], resulting in aberrantly high global levels of H3K36me2 [18]. NSD3 is amplified in primary breast carcinoma, bladder cancer, lung cancer, and liver cancer [12,16,25,35]. Abnormal fusion proteins containing NSD family members, including NSD1-NUP98 and NSD3-NUP98 fusions, increase H3K36 methylation, leading to acute myeloid leukemia [24][25][26][27][28].…”

“…The NSD proteins are oncogenes highly expressed in numerous pathological conditions and are considered attractive novel therapeutic targets in cancers [2,[9][10][11][12][13][14][15][16][17][18][19][20]. The amplification of NSD1 has been reported in multiple myeloma, lung cancer, neuroblastoma and glioblastoma.…”

“…Therefore, the inhibition of NSD members by small molecules represents a valuable therapeutic strategy in several human cancers where elevated levels of NSD members have been reported [2,4,5,12,14,17,18,26,32,33,[43][44][45].…”