# The Interaction of DMRTA2 with HSP90β Inhibits p53 Ubiquitination and Activates the p53 Pathway to Suppress the Malignant Progression of Non-Small-Cell Lung Cancer

## TL;DR

This study shows that DMRTA2 interacts with HSP90β to stabilize p53 in non-small-cell lung cancer, potentially offering a new therapeutic target.

## Contribution

The novel finding is that DMRTA2 inhibits p53 ubiquitination by binding HSP90β, thereby activating the p53 pathway to suppress lung cancer progression.

## Key findings

- DMRTA2 is highly expressed in NSCLC tissues and correlates with poor prognosis.
- DMRTA2 binds HSP90β, blocking its interaction with p53 to suppress p53 ubiquitination and nuclear export.
- This p53 pathway activation inhibits lung cancer cell proliferation and invasion.

## Abstract

Background: Lung cancer, predominantly NSCLC (80%), has a poor prognosis due to late diagnosis and limited treatment efficacy. DMRTA2 (DMRT5), a transcription factor linked to neural/germ cell development, is overexpressed in NSCLC per TCGA data, indicating its potential role in tumorigenesis and as a therapeutic target. Methods: Conduct a comprehensive search of the relevant theoretical foundations. Based on this, differential expression analysis will be performed using the DESeq2 package in R on RNA-seq data from lung adenocarcinoma and lung squamous cell carcinoma in the TCGA database. The research will then employ various methods, including CRISPR genome editing, MTS assay, flow cytometry, Western blot, co-immunoprecipitation, immunofluorescence, and qRT-PCR. Results: Through experimental validation, we found that DMRTA2 mRNA is highly expressed in non-small-cell lung cancer (NSCLC) tissues and is negatively correlated with poor prognosis. DMRTA2 binds to HSP90β, inhibiting the interaction between HSP90β and p53, thereby suppressing p53 ubiquitination and nuclear export. This activates the p53 pathway, inhibiting the proliferation and invasion of lung cancer cells. Conclusions: In NSCLC, DMRTA2 acts as a context-dependent regulator, stabilizing wild-type p53 through competitive HSP90β binding to suppress tumors, while in p53-compromised cells, potentially engaging HSP90β or alternative pathways to promote malignancy. Its dual localization and transport interactions reveal multifunctional, stress-responsive roles beyond transcription.