DHX33 Transcriptionally Controls Genes Involved in the Cell Cycle

Abstract

The RNA helicase DHX33 has been shown to be a critical regulator of cell proliferation and growth. However, the underlying mechanisms behind DHX33 function remain incompletely understood. We present original evidence in multiple cell lines that DHX33 transcriptionally controls the expression of genes involved in the cell cycle, notably cyclin, E2F1, cell division cycle (CDC), and minichromosome maintenance (MCM) genes. DHX33 physically associates with the promoters of these genes and controls the loading of active RNA polymerase II onto these promoters. DHX33 deficiency abrogates cell cycle progression and DNA replication and leads to cell apoptosis. In zebrafish, CRISPR-mediated knockout of DHX33 results in downregulation of cyclin A2, cyclin B2, cyclin D1, cyclin E2, cdc6, cdc20, E2F1, and MCM complexes in DHX33 knockout embryos. Additionally, we found the overexpression of DHX33 in a subset of non-small-cell lung cancers and in Ras-mutated human lung cancer cell lines. Forced reduction of DHX33 in these cancer cells abolished tumor formation in vivo. Our study demonstrates for the first time that DHX33 acts as a direct transcriptional regulator to promote cell cycle progression and plays an important role in driving cell proliferation during both embryo development and tumorigenesis.

DHX33 Interacts with AP-2β To Regulate Bcl-2 Gene Expression and Promote Cancer Cell Survival

“…We and others have previously found that knockdown of DHX33 leads to apoptosis in human cancer cells (8,11). However, the underlying mechanism of this process remains obscure.…”

“…Overexpression of DHX33 was found in several human cancers, such as lung, liver, lymphoma, and glioblastoma (10)(11)(12)(13). Analysis of patients with non-small-cell lung cancer indicated that DHX33 is highly expressed in 30% (28/95) of cases (11). Elevated expression of DHX33 was also observed in 66.3% (345/520) of hepatocellular carcinoma patients, and low DHX33 expression correlated significantly with longer survival time (12).…”

A 54‐kDa short variant of DHX33 functions in regulating mRNA translation

“…Melt curve analysis confirmed that single products were amplified. The primers that were used to analyze the changes in mRNA levels for genes involved in the cell cycle (Figure f) were shown previously (Yuan et al, ). The primers that were used to analyze mRNA levels in Figure d were shown below.…”

Function of DHX33 in promoting Warburg effect via regulation of glycolytic genes

“…DHX33 was then shown to promote the assembly of the elongation‐competent 80 S ribosome on selective mRNA (Zhang, You, Wang, & Weber, 2015). Additionally, DHX33 interacts with genetic elements to promote gene transcription for a subset of genes involved in the cell cycle, apoptosis and migration (Fu, Liu, Wang, Yuan, & Zhang, 2017; Wang, Feng, Yuan, Weber, & Zhang, 2019; Yuan et al, 2016). Given the important role of DHX33 in cell proliferation, it succumbs to multiple levels of regulation, transcriptionally, translationally, and posttranslationally (Fraile et al, 2018; Fu et al, 2017; Zhang, Saporita, & Weber, 2013).…”

“…Over 80% of all cancer cells have enhanced glycolysis, a hallmark of cancer cells. RNA helicase DHX33 has been found to be highly expressed in multiple human cancers (Fu et al, 2017; Tian et al, 2016; Yuan et al, 2016). Cancer cells with deficient DHX33 were frequently observed to metabolize glucose at a slower rate as compared to the control group.…”