Givinostat blocks colorectal cancer growth by silencing ADAM12 through miR-1938

Colorectal cancer remains one of the deadliest malignancies worldwide, and the search for drugs that can shut down tumor growth with minimal toxicity has never been more urgent. Now, a team of researchers from Xinjiang University and collaborating hospitals in China has reported that ITF2357, a histone deacetylase inhibitor better known by its clinical name givinostat, exerts potent anti-tumor activity against colorectal cancer through an unexpected molecular route. Writing in Molecular Biology Reports, the group led by Zeyidan Jiapaer shows that the drug works by boosting a tiny regulatory RNA called miR-1938, which in turn suppresses a cancer-promoting protein known as ADAM12. The discovery offers a fresh mechanistic explanation for how an epigenetic drug can reprogram the gene expression machinery of cancer cells and stall their proliferation.

Histone deacetylase inhibitors represent one of the most actively explored classes of epigenetic anticancer agents. These drugs block enzymes that remove acetyl groups from histone proteins, the spools around which DNA is wound. When acetylation is preserved, chromatin stays in an open, transcriptionally permissive state, allowing genes that restrain tumor growth to be expressed. Aberrant deacetylation is a hallmark of many cancers, including colorectal cancer, where it silences tumor suppressor pathways and promotes uncontrolled cell division. Prior studies have shown that HDAC inhibitors can trigger cell cycle arrest, differentiation, and even programmed cell death in a range of tumor types, from glioblastoma to gastric cancer, and givinostat itself has already been tested in humans for inflammatory and blood disorders.

To probe how ITF2357 affects colorectal cancer cells, the researchers turned to CT26, a mouse colon carcinoma cell line widely used in preclinical oncology. In laboratory cultures, the drug significantly reduced cell viability and proliferation and dramatically impaired the ability of cells to form colonies, a measure of long-term reproductive fitness. Flow cytometry analysis of the cell cycle revealed that treated cells accumulated in the G0/G1 phase, the resting and early growth stage of the cell cycle, indicating that ITF2357 prevents cells from committing to DNA replication. This kind of arrest is a classic anti-proliferative signature and suggests the drug halts tumor expansion by keeping cells locked out of the division program rather than by causing immediate toxicity.

The team then moved from the dish to living organisms. They established subcutaneous CT26 tumors in female BALB/c mice and treated the animals with ITF2357. The drug markedly suppressed tumor growth over the course of the experiment. Critically, the treated mice showed no loss of body weight and no observable damage to liver or kidney tissue, two organs whose health is a standard barometer of systemic toxicity. This safety profile is particularly notable because many anticancer agents fail at this hurdle, and it suggests that ITF2357 can discriminate between tumor cells and normal tissue at the doses tested, at least in this model.

What makes the new study stand out is the depth of its molecular detective work. Rather than stopping at the observation that the drug works, the researchers deployed a multi-omics strategy to trace exactly how it acts. They performed miRNA sequencing to catalogue the small RNAs whose expression changes after treatment, mRNA sequencing to capture the downstream gene expression shifts, and ATAC-seq, a technique that maps open chromatin regions genome-wide and reveals where the transcriptional machinery has gained or lost access to DNA. Integrating these three layers of data allowed the team to pinpoint candidate regulatory molecules that connect the epigenetic action of the drug to its biological effects.

The analysis converged on a striking finding: ITF2357 treatment upregulated miR-1938, a microRNA that had not previously been implicated in the response to HDAC inhibitors in colorectal cancer. MicroRNAs are short non-coding RNAs, roughly 20 to 24 nucleotides long, that regulate gene expression after transcription. Each microRNA binds to complementary sequences in the 3-prime untranslated region, or 3′-UTR, of target messenger RNAs, blocking their translation into protein or hastening their degradation. Through this post-transcriptional gatekeeping, a single microRNA can restrain an entire network of cancer-promoting genes. The researchers validated the interaction experimentally using a dual-luciferase reporter assay, which confirmed that miR-1938 binds directly to the 3′-UTR of ADAM12 messenger RNA and suppresses its output.

ADAM12 belongs to a family of transmembrane metalloproteases involved in shedding growth factors, remodeling the extracellular matrix, and driving invasive behavior in tumors. Elevated ADAM12 expression has been linked to poor outcomes in liver cancer and colon adenocarcinoma, and it has been implicated in tumor angiogenesis through STAT3 signaling. The new study adds a crucial layer to this picture by showing that ADAM12 is a direct functional target of the drug response. When the researchers knocked down ADAM12 with RNA interference in CT26 cells, the effects mirrored those of ITF2357 treatment: proliferation dropped and cells accumulated in the G0/G1 phase. This phenocopy experiment is a powerful piece of evidence that suppressing ADAM12 is not merely a side effect of the drug but a central mechanism through which it stalls tumor growth.

The clinical relevance of the axis was reinforced by prognostic data. The team found that colorectal cancer patients with high ADAM12 expression in their tumors had significantly worse outcomes, consistent with earlier reports that ADAM12 upregulation correlates with poor survival and altered immune cell infiltration in colon adenocarcinoma. This means the miR-1938/ADAM12 axis is not just a laboratory curiosity but a molecular signature that tracks with real patient prognosis, raising the possibility that ADAM12 could serve as both a biomarker for identifying patients likely to benefit from HDAC inhibitor therapy and a therapeutic target in its own right.

From a translational standpoint, the study arrives at an interesting moment for givinostat. The drug has a documented pharmacokinetic and safety profile from phase 1 trials in humans, where it was administered orally and shown to modulate inducible cytokine responses. It has been explored in chronic myeloproliferative neoplasms carrying the JAK2V617F mutation, in acute myeloid leukemia cells, and in glioblastoma models where it reversed transformed phenotypes and countered cancer stemness. The new colorectal cancer data extend this portfolio and, importantly, identify a specific microRNA-mediated mechanism that could be monitored in future trials as a pharmacodynamic readout of drug activity.

The researchers caution that their findings come from cell culture and a mouse xenograft model, and that translating these results into human therapy will require further validation, including studies in patient-derived models and eventually clinical trials. Nevertheless, the work establishes a clear causal chain from an epigenetic drug to a microRNA to a cancer-driving protease to a cell cycle checkpoint, and it does so with the kind of multi-omics rigor that is increasingly expected in modern cancer pharmacology. For a disease as prevalent and lethal as colorectal cancer, the identification of a druggable axis that can be engaged by an already clinically tested molecule is a meaningful step forward, and it provides a foundation for exploring ITF2357 as a therapeutic option in patients whose tumors depend on the ADAM12 pathway.

Subject of Research: Pharmacology and molecular oncology of colorectal cancer

Article Title: ITF2357 exerts anti‑tumor activity in colorectal cancer via the miR‑1938/ADAM12 axis

Article References: Wang, T., Zhang, L., Yakupu, Z., Shi, X., Maimaiti, Y., Salikebai, B., Mahemuti, M., Xiao, H., Daoken, Y., Wang, Z., Zhang, B., & Jiapaer, Z. (2026). ITF2357 exerts anti‑tumor activity in colorectal cancer via the miR‑1938/ADAM12 axis. Molecular Biology Reports, 53(1), Article 1753. https://doi.org/10.1007/s11033-026-12944-y

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12944-y

Keywords: colorectal cancer, givinostat, ITF2357, HDAC inhibitor, miR-1938, ADAM12, cell cycle arrest, epigenetics, microRNA, multi-omics, tumor suppressor, drug mechanism