AC1Q3QWB

Endometrial cancer (EC) is a common malignancy of the female reproductive system, with an escalating incidence. Recurrent/metastatic EC presents a poor prognosis. The interaction between the long non-coding RNA (lncRNA) HOTAIR and the polycomb repressive complex 2 (PRC2) induces abnormal silencing of tumor suppressor genes, exerting a pivotal role in tumorigenesis. We have previously discovered AC1Q3QWB (AQB), a small-molecule compound targeting HOTAIR-EZH2 interaction. In the present study, we unveil that AQB selectively hampers the interaction between HOTAIR and EZH2 within EC cells, thus reversing the epigenetic suppression of tumor suppressor genes. Furthermore, our findings demonstrate AQB's synergistic effect with tazemetostat (TAZ), an EZH2 inhibitor, significantly boosting the expression of CDKN1A and SOX17. This, in turn, induces cell cycle arrest and impedes EC cell proliferation, migration, and invasion. In vivo experiments further validate AQB's potential by enhancing TAZ's anti-tumor efficacy at lower doses. Our results advocate AQB, a recently discovered small-molecule inhibitor, as a promising agent against EC cells. When combined with TAZ, it offers a novel therapeutic strategy for EC treatment.

Colorectal cancer (CRC) is a common malignancy with high mortality and few effective therapeutic measures. Gut microbiota dysbiosis and chronic inflammation might contribute to the development of CRC. The present study aimed to explore the effect of AC1Q3QWB (AQB) on colon carcinogenesis in vivo.

A mouse colon cancer model was constructed by intraperitoneal injection of 10 mg/kg of Azoxymethane (AOM) and 2 % dextran sodium sulfate (DSS) in drinking water. Mice were randomly assigned to four groups: normal control (NC), AOM/DSS (model control, MC), DMSO + AOM/DSS (DMSO), and AQB + AOM/DSS (AQB). Mice in the AQB group were treated with an intraperitoneal injection of AQB (50 mg/kg) after successful modeling. Then, the disease activity index (DAI) of colitis was analyzed. Colon tissues were collected for hematoxylin-eosin, immunohistochemistry, and microscopic and histological evaluation. Stool samples were collected for microbiota analysis by 16S rRNA sequencing. Blood samples were analyzed by flow cytometry to investigate the inflammatory response.

In AOM/DSS-induced CRC mouse model, AQB treatment dramatically reduced the number and size of colon tumors. AQB treatment enhances CD8+⁺T cell response and triggers the accumulation of CD4+⁺CD25+⁺Foxp3+⁺Regulatory T cells (Tregs) and B cells. AQB regulated the structure and composition of the gut microbiota, which decreased the Firmicutes/Bacteroidetes ratio at the phylum level and increased the abundance of probiotics.

AQB has potent antitumor activity against colorectal cancer in vivo by a mechanism that might involve modulation of the immune system and alteration of the intestinal microbiota.