Endometrial cancer, also known as Uterine Corpus Endometrial Carcinoma (UCEC), is the most common malignancy of the female reproductive system, with a global incidence rate of approximately 4.4% (1, 2). The increasing incidence, mortality rates and 10-20% developing distant recurrence, present a significant public health challenge of UCEC (3). This highlights the urgent need for dissecting the molecular mechanisms driving UCEC and the exploring novel therapeutic methods.

One potential molecular target is RCOR2 (REST corepressor 2), a nuclear transcription co-repressor that functions primarily as a transcriptional repressor and is involved in maintaining the pluripotency of embryonic stem cells and regulating neurogenesis (4, 5). Preliminary bioinformatics analyses have indicated that RCOR2 is overexpressed in various cancers, including UCEC. This overexpression has been associated with poor prognosis in cancer patients (6, 7). Additionally, RCOR2 has been implicated in the regulation of immune responses (5, 8, 9), further suggesting its potential role in tumorigenesis and cancer progression.

Recent studies have provided insights into the mechanisms by which RCOR2 may contribute to cancer. In acute myeloid leukemia (AML), RCOR2 was found to be upregulated in B7-H4-null cells, and its knockdown resulted in reduced leukemogenesis (6, 10). This suggests that RCOR2 may promote cancer cell survival and proliferation by modulating key signaling pathways. In the context of UCEC, however, the specific functions and mechanisms of RCOR2 remain to be elucidated.

To address this gap in knowledge, this study aims to investigate the expression and functional role of RCOR2 in UCEC. Specifically, we seek to determine whether RCOR2 is upregulated in UCEC tissues and cell lines and to assess its impact on UCEC cell viability and proliferation. By investigating the expression and functional role of RCOR2 in UCEC, this study provided valuable insights of RCORs in UCEC progression.

This study provides the first comprehensive evidence that RCOR2 plays an oncogenic role in UCEC, particularly by regulating tumor cell proliferation, and may serve as a novel biomarker and therapeutic target. RCOR2 was significantly upregulated in UCEC tissues at both mRNA and protein levels, and its expression correlated with key clinical features including advanced stage, higher histologic grade, and lymph node metastasis, suggesting its involvement in tumor progression. These findings are consistent with emerging literature implicating transcriptional co-repressors in cancer development, such as RCOR1 and LSD1/CoREST complexes, which are known to modulate chromatin states and transcriptional programs in malignancies (6, 7, 12).

The overexpression of RCOR2 in endometrial cancer tissues and its correlation with advanced clinical stages, higher histological grades, and lymph node metastasis suggest that RCOR2 may drive tumor progression through various molecular pathways. RCOR2 has been shown to regulate the expression of genes involved in cell cycle progression, apoptosis, and differentiation, all of which are crucial processes in cancer development and progression (4, 12–14). Additionally, RCOR2 has been implicated in the regulation of immune responses, further suggesting its potential role in tumorigenesis and cancer progression (5, 8, 9).

The positive correlation between RCOR2 and proliferation markers MKI67, CCND1, and PCNA underscores its potential role in driving proliferative signaling pathways in UCEC. These genes are classical indicators of cell proliferation and have been shown to be associated with poor prognosis in multiple cancers, including breast, prostate, and cervical cancers (15–17). Functionally, RCOR2 knockdown suppressed, and overexpression promoted, UCEC cell proliferation in vitro, confirmed by CCK8, colony formation, and qPCR assays—supporting a causative rather than correlative role. Specifically, RCOR2 appears to regulate the cell proliferation-related genes, such as MKI67, CCND1, and PCNA, which are known markers of cell proliferation and have been implicated in the aggressive behavior of various cancers​​​​ (18–20).

The association between RCOR2 expression and poor prognosis in endometrial cancer patients is consistent with studies on other transcriptional regulators in cancer. For instance, studies have shown that downregulation of RCOR1 and RCOR2 in osteoarthritic chondrocytes contributes to increased expression of catabolic enzymes through upregulation of HES1 (12). This indicates a broader role for RCOR proteins in regulating gene expression and cellular behavior in pathological conditions.

The diagnostic value of RCOR2 was further confirmed by ROC analysis, which demonstrated strong sensitivity and specificity for distinguishing tumor aggressiveness, making RCOR2 a candidate diagnostic biomarker. This is particularly relevant given the current limitations in early detection of aggressive UCEC subtypes.

While our findings robustly demonstrate RCOR2’s role in promoting proliferation and its positive correlation with canonical proliferation markers (MKI67, CCND1, and PCNA), the underlying molecular mechanisms remain to be fully elucidated. Mechanistically, RCOR2 has been implicated in transcriptional repression networks involving REST and HDACs (21, 22), and may influence endometrial cancer progression by modulating epigenetic landscapes that control proliferation and differentiation pathways. While our findings establish a strong link between RCOR2 expression and tumor behavior, the precise molecular mechanisms by which RCOR2 modulates transcription in UCEC remain to be elucidated.

RCOR2, a member of the CoREST family of transcriptional co-repressors, is known to interact with chromatin-modifying complexes, such as LSD1 and HDACs (23), suggesting a potential role in epigenetic regulation of gene expression. It is plausible that RCOR2 promotes proliferation not only by upregulating proliferation-associated genes but also through repression of cell cycle inhibitors, such as CDKN1A (p21) or CDKN1B (p27), thereby facilitating G1/S transition (24). Additionally, RCOR2 may influence key regulatory pathways involved in cell cycle progression, including E2F and MYC signaling networks, either directly or via modulation of histone methylation and acetylation states (24, 25).

Emerging studies on epigenetic regulators in gynecologic cancers offer valuable parallels. For instance, recent work highlights the role of epigenetic remodeling in endometrial cancer proliferation and resistance, underscoring the importance of chromatin context in driving oncogenic programs (26). Similarly, findings implicate epigenetic dysregulation through histone modifiers in promoting tumor aggressiveness in breast Cancer and other gynecological cancers (27). These insights raise the possibility that RCOR2, through its association with LSD1/CoREST complexes, may contribute to the silencing of tumor suppressor genes or the activation of oncogenic enhancers.

Future investigations into RCOR2’s genomic binding sites, transcriptomic targets, and interaction partners—such as LSD1, REST, or G9a—could provide a more comprehensive understanding of its role in UCEC. Such studies may reveal whether its oncogenic role extends beyond proliferation to include pathways governing differentiation, apoptosis, or immune evasion. Exploring these mechanisms could yield novel therapeutic targets or biomarkers for aggressive subtypes of UCEC.

Although this study did not record menstrual cycle phases for premenopausal patients, their limited representation (15 of 174, 8.6%) minimizes potential impact on overall results. Over 75% of the cohort were postmenopausal, reducing variability from hormonal fluctuations. The study’s primary focus was on pathological differences between tumor and adjacent normal tissues, with RCOR2 found to be significantly overexpressed in endometrial cancer and associated with adverse clinicopathological features, including stage, grade, and lymph node metastasis. Given that tumor-related epigenetic dysregulation and abnormal cell proliferation likely exert stronger effects on RCOR2 expression than physiological hormonal changes, and considering the paired tissue design from the same patients, potential confounding from menstrual cycle phases is minimal. Thus, the key conclusion regarding RCOR2 overexpression in endometrial cancer and its clinical relevance remains robust.

Despite these promising results, several limitations exist. First, the study relied primarily on one cell line (ISK), which, while representative of UCEC, may not fully capture tumor heterogeneity. Future studies using multiple UCEC cell lines and patient-derived xenografts (PDX) or organoids would strengthen translational relevance. Second, in vivo validation is essential to confirm the tumorigenic role of RCOR2 and evaluate its potential as a therapeutic target.

In conclusion, our study identifies RCOR2 as a key contributor to UCEC proliferation and progression, highlights its potential diagnostic utility, and opens avenues for mechanistic and therapeutic exploration. Future work should focus on elucidating the RCOR2-centered transcriptional networks and assessing the efficacy of RCOR2-targeted strategies in vivo.