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

Abstract

The RNA helicase DHX33 has been found to be overexpressed in human cancers, where it promotes cancer development. Previous reports have shown that DHX33 deficiency caused cancer cell apoptosis, but the underlying mechanism remains unknown. In this study, we discovered that DHX33 regulates Bcl-2 family protein expression. In multiple human cancer cell lines, DHX33 was found to stimulate the transcription of Bcl-2. Mechanistically, we found that DHX33 interacts with the AP-2␤ transcription factor and acts as a coactivator to stimulate Bcl-2 gene transcription. DHX33 deficiency abolished the loading of AP-2␤ onto the promoter of Bcl-2 and thereby reduced the recruitment of active RNA polymerase II during transcription initiation. Acute knockdown of DHX33 in multiple human cancer cells caused decreased Bcl-2 protein level, which ultimately triggered mitochondrionmediated cellular apoptosis. In addition, we found that normal human lung and mammary epithelial cells were less sensitive to acute DHX33 knockdown, implying that cancer cells are uniquely responsive to DHX33 reduction. These data support the notion that disruption of DHX33 function could be an important application for cancer therapy.

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

“…As shown in Figure 5b,c, we found DHX33 interacts with Gadd45a. Transcription factor AP‐2β has been identified as an interacting partner of DHX33 before (J. Wang, Feng, et al, 2019), here we confirmed the interaction between them also in glioblastoma cells. The interaction between Gadd45a and DHX33 cannot be influenced by RNase H, indicating that the binding between them is independent of RNA in cells.…”

“…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).…”

DEAD-Box RNA Helicases in Cell Cycle Control and Clinical Therapy

“…DHX33 is required for promoting cell cycle progression at the G1-to-S phase transition, which is overexpressed in several types of human cancers, such as lung cancers, hepatocellular carcinoma, lymphoma, colon cancer, and glioblastoma ( Table 1 ) [ 16 , 51 , 52 , 53 , 54 ]. A deficiency of DHX33 induced a significant increase of G1-phase cells and a marked decrease of S-phase cells in different cancer cells [ 51 , 53 , 54 , 55 ]. Mechanically, DHX33 recruits active RNA polymerase II (Pol II) to the promoters of many cell-cycle-related genes, including cyclin E2, cyclin D1, E2F1, MMP9, MCMs, CDC6, and CDC20, and initiates the transcription of those genes [ 53 , 55 ] ( Figure 3 ).…”

“…DHX33 plays a significant role in ribosome RNA synthesis and mRNA translation DHX33 promotes numerous cellular processes, including cell cycle progression, apopto sis, and migration, by promoting the transcription of a subset of genes, including Bcl MMP9, MMP14, and urokinase-type plasminogen activator [51,52]. DHX33 is required fo promoting cell cycle progression at the G1-to-S phase transition, which is overexpresse in several types of human cancers, such as lung cancers, hepatocellular carcinoma, lym phoma, colon cancer, and glioblastoma (Table 1) [16,[51][52][53][54]. A deficiency of DHX33 in duced a significant increase of G1-phase cells and a marked decrease of S-phase cells i different cancer cells [51,[53][54][55].…”

Targeting RNA helicase DHX33 blocks Ras‐driven lung tumorigenesis in vivo

“…DHX33 is further found to be actively involved in mRNA translation 20 and mRNA transcription via associating with gene promoters. In lung cancer cells, DHX33 was found to regulate a subset of genes though altering epigenetic marks 18,19,21,22 …”