ONECUT2 (One Cut Homeobox 2)

These findings provide preliminary evidence supporting further investigation of sex-specific approaches to BC management.

Notably, a four-gene panel (ONECUT2, SOX1, TWIST1 and NKX2-4) significantly improved the detection performance, with an AUC of 0.971 and an accuracy of 92.39%. Our results provide three new DNA methylation markers for BLCA and propose a urine-based DNA methylation detection panel for non-invasive clinical diagnosis.

Pharmacological inhibition of REV-ERBα exhibits high potency in blocking the growth of NEPC tumors including patient-derived xenografts. Our findings reveal that therapy-induced LP development entails a coordinated induction of a network of LP drivers and that REV-ERBα is an unexpected master regulator of the network and a promising therapeutic target for treatment of advanced prostate cancer such as NEPC.

Further mechanism studies have shown that the transcription factor ONECUT2 is also highly expressed in CRC and indicates a poor prognosis, and it can directly activate its transcription by binding to the ADAMTS14 promoter region. In conclusion, this study has revealed a novel mechanism by which the ONECUT2/ADAMTS14/Wnt axis regulates the stemness of CRC cells, providing a potential molecular target for targeted intervention.

OC2 can be targeted directly with a family of novel small molecule inhibitors that show therapeutic efficacy in vivo in prostate, breast and gastric cancer models, including regression of established distant metastases in mice. These findings suggest that inhibition of OC2 clinically may confer substantial therapeutic benefit in some aggressive malignancies, including in localized, hormone-sensitive disease.

LINC01949 suppresses rituximab resistance in DLBCL by promoting H3K27me3-dependent silencing of ONECUT2. These findings highlight the LINC01949-H3K27me3-ONECUT2 axis as a key epigenetic pathway and suggest potential targets to overcome resistance in DLBCL.

Our study unveiled the tumor-promoting role of TRMT61A in CRC via the m1A-ONECUT2-SOS1-MAPK/ERK pathway. Targeting TRMT61A showed promise as a therapeutic strategy for treating CRC.

In addition, OC2 upregulates non-NE programs through activation of c-MYC and Notch signaling. We also demonstrate that OC2 is required for growth and survival of SCLC cells and that it can be targeted with a small molecule inhibitor that acts synergistically with the standard combination of cisplatin and etoposide, providing a novel therapeutic strategy for OC2 active SCLC tumors.

Our study demonstrates that YTHDF2-mediated m6A modification of ONECUT2 results in stemness and oxaliplatin resistance in GC through transcriptionally activating TFPI, which provides a novel therapeutic target against oxaliplatin-resistant GC.

The recent identification of several other key novel drivers of NE transdifferentiation, including MYCN, ASCL1, BRN2, ONECUT2, and FOXA2, further elucidates the complex regulatory networks and pathways involved in this process. We suggest that, given the multifactorial nature of NEPC, novel therapeutic strategies that combine multiple modalities are essential to overcome therapeutic resistance and improve patient outcomes.

Moreover, the overexpression of OC2 or SKP2 in the knockout HCC cell line clearly inhibited the acetylation level of p53 and reduced cell apoptosis. This study revealed that OC2 could regulate the apoptosis of HCC cells through the SKP2/p53/p21 axis, which may provide some therapeutic targets for HCC in the clinic.