Inhibiting NAT10 suppresses hepatocellular carcinoma progression by reducing Nrf2 mRNA stability and increasing
1School of Life Sciences, Shanghai University, 99 Shangda Road, Shanghai, 200444, China.
Abstract:
Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide, and despite advances in systemic therapies, resistance to targeted therapies such as Sorafenib significantly limits clinical benefit and contributes to poor outcomes. The mechanisms that enable HCC cells to withstand oxidative stress and evade therapy remain incompletely understood. Here, we identify an RNA regulatory role of NAT10 in sustaining redox homeostasis in HCC. We show that NAT10 stabilizes Nrf2 mRNA, a master regulator of antioxidant responses, thereby maintaining Nrf2 protein abundance and reducing intracellular reactive oxygen species (ROS) levels in HCC cells. Genetic silencing or pharmacologic inhibition of NAT10 disrupts this regulatory axis, leading to elevated ROS accumulation, induces DNA damage, and enhances apoptosis. Importantly, NAT10 knockdown markedly sensitizes HCC cells to Sorafenib, and simultaneous inhibition of NAT10 and Nrf2 exhibits a synergistic pro-apoptotic effect, suggesting that oxidative stress overload is a key vulnerability created by targeting this pathway. Together, these finding uncover a NAT10-Nrf2 RNA stability axis that enhances antioxidant capacity and therapeutic tolerance in HCC, and highlight NAT10 as a promising target for overcoming drug resistance and improving treatment response.
Insights
Researchers found that NAT10 stabilizes Nrf2 mRNA, maintaining antioxidant responses in hepatocellular carcinoma (HCC). Inhibiting NAT10 increases oxidative stress and sensitizes HCC cells to Sorafenib, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality globally.
- Therapeutic resistance, particularly to targeted agents like Sorafenib, significantly hinders effective treatment for HCC.
- The underlying mechanisms of oxidative stress resistance and therapy evasion in HCC are not fully understood.
Purpose of the Study:
- To investigate the RNA regulatory role of NAT10 in maintaining redox homeostasis within HCC.
- To elucidate the mechanism by which NAT10 influences the Nrf2 pathway and its impact on HCC cell survival and drug response.
Main Methods:
- Utilized genetic silencing (knockdown) and pharmacologic inhibition of NAT10 in HCC cell models.
- Assessed intracellular reactive oxygen species (ROS) levels, DNA damage, and apoptosis.
- Evaluated the combined effects of NAT10 inhibition and Sorafenib treatment, with and without Nrf2 inhibition.
Main Results:
- NAT10 was identified to stabilize Nrf2 mRNA, crucial for antioxidant responses in HCC.
- NAT10 inhibition led to increased ROS, DNA damage, and apoptosis in HCC cells.
- NAT10 knockdown significantly sensitized HCC cells to Sorafenib, and combined NAT10/Nrf2 inhibition showed synergistic apoptosis.
Conclusions:
- A NAT10-Nrf2 RNA stability axis enhances antioxidant capacity and therapeutic tolerance in HCC.
- Targeting NAT10 presents a promising strategy to overcome Sorafenib resistance and improve treatment outcomes in HCC.
- Exploiting oxidative stress overload by inhibiting this pathway represents a key vulnerability in HCC treatment.
Related Concept Videos
02:26NF-κB-dependent Signaling Pathway
NF-κB-dependent Signaling Mechanism
The...
02:23Abnormal Proliferation
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...