# LDOC1 connects histone H2B monoubiquitination to tumor cell plasticity in non-small cell lung cancer

## TL;DR

This study shows how the protein LDOC1 controls histone modifications in lung cancer cells, affecting their ability to spread and how this relates to patient outcomes.

## Contribution

The study reveals a novel mechanism by which LDOC1 regulates histone H2B monoubiquitination and tumor cell plasticity in NSCLC.

## Key findings

- LDOC1 interacts with H2Bub1 and PSMA1 to promote proteasomal degradation, limiting global H2Bub1 levels.
- LDOC1 loss enhances TGF-β–induced epithelial–mesenchymal transition plasticity and promotes a hybrid E/M phenotype.
- High H2Bub1 levels correlate with poor survival in NSCLC patients and are linked to KRAS-mutant lung adenocarcinoma.

## Abstract

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, partly because epigenetic dysregulation drives tumor progression and metastasis. We previously showed that leucine zipper downregulated in cancer 1 (LDOC1) modulates the metastatic potential of NSCLC cells. The structural features of LDOC1 suggest that it can interact with nuclear histones, and although it lacks a canonical nuclear localization signal, it predominantly localizes to the nucleus in NSCLC cells; its loss causes broad transcriptomic changes, supporting a role for LDOC1 as an epigenetic regulator acting through histone modifications.

The levels of histone proteins were assessed in NSCLC cell lines with either LDOC1 knockdown or ectopic expression. Transcriptomic profiling, ChIP-seq, ATAC-seq, MNase digestion assays, flow cytometry, coimmunoprecipitation, proximity ligation assays, immunofluorescence staining, immunohistochemistry, and functional assays were conducted. Clinical relevance was analyzed with archived NSCLC samples and using datasets from the UCSC Xena database.

LDOC1 interacts with histone H2B and H2Bub1 as well as with PSMA1 to promote their proteasomal degradation, thereby limiting global H2Bub1 levels. Despite increasing global H2Bub1 abundance, LDOC1 knockdown caused a pronounced loss of chromatin-bound H2Bub1 and enhanced chromatin compaction, effects that were partially mediated by the LDOC1–THAP12 interaction. THAP12 overexpression increased LDOC1 recovery in nuclear histone fractions. Integrated transcriptomic and epigenomic analyses revealed that the LDOC1–H2Bub1 axis regulates key metastasis-related genes involved in cytoskeletal remodeling, cell adhesion, and epithelial–mesenchymal (E–M) transition. Functionally, LDOC1 loss enhanced TGF-β–induced E–M plasticity, promoted a hybrid E/M phenotype, reduced adhesion, and altered migration dynamics. In clinical samples, H2Bub1 was significantly upregulated in spread through air spaces (STAS) and inversely correlated with LDOC1 expression. High H2Bub1 expression predicted shorter progression-free survival in EGFRᵂᵀ NSCLC patients receiving chemotherapy, and TCGA data linked LDOC1 downregulation to KRAS-mutant lung adenocarcinoma.

LDOC1-mediated chromatin remodeling, through regulation of H2Bub1 recruitment and turnover, represents a key mechanism promoting NSCLC progression. The LDOC1–H2Bub1 axis, potentially involving THAP12, shapes chromatin accessibility and metastatic transcriptional programs, providing mechanistic and clinical insights into tumor aggressiveness and therapeutic response.

The online version contains supplementary material available at 10.1186/s12964-025-02607-z.

Non-small cell lung cancer (NSCLC) is one of the most common and deadly forms of cancer. In this study, we explored the role of a protein called LDOC1 in NSCLC and how it works together with another protein, THAP12. We found that LDOC1 can bind to histone proteins—molecules that help package DNA in the cell nucleus—and works with another protein to break down a modified form of histone H2B called H2Bub1. In this way, LDOC1 normally helps keep H2Bub1 levels under control. THAP12 appears to help bring LDOC1 to chromatin in the nucleus, strengthening this regulatory effect.

When LDOC1 was lost in NSCLC cells, the total amount of H2Bub1 in the cell increased, but its proper distribution on DNA was disrupted. This led to DNA becoming more compact and altered the activity of many genes that control how cancer cells change shape, move, and spread. Without LDOC1, NSCLC cancer cells more easily switch between different shapes (epithelial and mesenchymal states) and adopt a flexible “in-between” state that is linked to greater invasiveness.

In tumor samples from patients, high H2Bub1 levels were linked to areas where cancer had spread into nearby air spaces in the lung (a pattern called spread through air spaces, or STAS) and were associated with worse outcomes for patients receiving chemotherapy. Our findings suggest that LDOC1 and H2Bub1 could be used together as biomarkers to identify aggressive lung cancers and guide treatment choices, as well as provide new targets for therapy.

The online version contains supplementary material available at 10.1186/s12964-025-02607-z.