PARP1-DOT1L transcription axis drives acquired resistance to PARP inhibitor in ovarian cancer.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance poses a significant challenge in ovarian carcinoma (OC). While the role of DOT1L in cancer and chemoresistance is acknowledged, its specific role in PARPi resistance remains unclear. This study aims to elucidate the molecular mechanism of DOT1L in PARPi resistance in OC patients. METHODS: This study analyzed the expression of DOT1L in PARPi-resistant cell lines compared to sensitive ones and correlated it with clinical outcomes in OC patients. Comprehensive in vitro and in vivo functional experiments were conducted using cellular and mouse models. Molecular investigations, including RNA sequencing, chromatin immunoprecipitation (ChIP) and Cleavage Under Targets and Tagmentation (CUT&Tag) assays, were employed to unravel the molecular mechanisms of DOT1L-mediated PARPi resistance. RESULTS: Our investigation revealed a robust correlation between DOT1L expression and clinical PARPi resistance in non-BRCA mutated OC cells. Upregulated DOT1L expression in PARPi-resistant tissues was associated with diminished survival in OC patients. Mechanistically, we identified that PARP1 directly binds to the DOT1L gene promoter, promoting transcription independently of its enzyme activity. PARP1 trapping induced by PARPi treatment amplified this binding, enhancing DOT1L transcription and contributing to drug resistance. Sequencing analysis revealed that DOT1L plays a crucial role in the transcriptional regulation of PLCG2 and ABCB1 via H3K79me2. This established the PARP1-DOT1L-PLCG2/ABCB1 axis as a key contributor to PARPi resistance. Furthermore, we discovered that combining a DOT1L inhibitor with PARPi demonstrated a synergistic effect in both cell line-derived xenograft mouse models (CDXs) and patient-derived organoids (PDOs). CONCLUSIONS: Our results demonstrate that DOT1L is an independent prognostic marker for OC patients. The PARP1-DOT1L/H3K79me2-PLCG2/ABCB1 axis is identified as a pivotal contributor to PARPi resistance. Targeted inhibition of DOT1L emerges as a promising therapeutic strategy for enhancing PARPi treatment outcomes in OC patients.

BRD4 inhibition sensitizes cervical cancer to radiotherapy by attenuating DNA repair.

Cisplatin-based chemoradiotherapy is the recommended treatment for local advanced cervical cancer, but radioresistance remains one of the most important and unresolved clinical problems. Investigations have revealed aberrant epigenetic modifications as one of the chief culprits for the development of radioresistance. Here, we attempt to identify a radiosensitizer from an epigenetic drug synergy screen and explore the underlying mechanism. We integrated epigenetic inhibitors and radiotherapy in cervical cancer cell lines to identify potential radiosensitizers. We further verified the sensitization effect of the drug and the function of its target gene both in vitro and in vivo. Finally, we validated the clinical significance of its target gene in clinical cervical cancer specimens. We identified JQ1, a BRD4 inhibitor, as a potent radiosensitizer. Functional assays demonstrated that repressing BRD4 activity led to significant radiosensitization and potentiation of DNA damage in cervical cancer cell lines. By using RNA-seq to determine JQ1-mediated changes in transcription, we identified RAD51AP1 as a major BRD4 target gene involved in radiosensitivity. A dual-luciferase reporter assay and ChIP-qPCR showed that BRD4 binds to the promoter region of RAD51AP1 and promotes its transcription, whereas this activity was attenuated by BRD4 inhibition. The in vivo experiments also suggested a synergy between BRD4 inhibition and radiotherapy. High BRD4 expression was found to be related to a worse prognosis and radiation resistance. BRD4 inhibition sensitizes cervical cancer to radiotherapy by inhibiting RAD51AP1 transcription. The combination of JQ1 with radiotherapy merits further evaluation as a therapeutic strategy for improving local control in cervical cancer.

FBW7 suppresses ovarian cancer development by targeting the N6-methyladenosine binding protein YTHDF2.

BACKGROUND: The tumor suppressor FBW7 is the substrate recognition component of the SCF E3-ubiquitin ligase complex that mediates proteolytic degradation of various oncogenic proteins. However, the role of FBW7 in ovarian cancer progression remains inadequately understood. METHODS: IP-MASS, co-IP, immunohistochemistry, and western blotting were used to identify the potential substrate of FBW7 in ovarian cancer. The biological effects of FBW7 were investigated using in vitro and in vivo models. LC/MS was used to detect the m6A levels in ovarian cancer tissues. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of YTHDF2. RESULTS: We unveil that FBW7 is markedly down-regulated in ovarian cancer tissues and its high expression is associated with favorable prognosis and elevated m6A modification levels. Consistently, ectopic FBW7 inhibits ovarian cancer cell survival and proliferation in vitro and in vivo, while ablation of FBW7 empowers propagation of ovarian cancer cells. In addition, the m6A reader protein, YTHDF2, is identified as a novel substrate for FBW7. FBW7 counteracts the tumor-promoting effect of YTHDF2 by inducing proteasomal degradation of the latter in ovarian cancer. Furthermore, YTHDF2 globally regulates the turnover of m6A-modified mRNAs, including the pro-apoptotic gene BMF. CONCLUSIONS: Our study has demonstrated that FBW7 suppresses tumor growth and progression via antagonizing YTHDF2-mediated BMF mRNA decay in ovarian cancer.

A Population-Based Study on Liver Metastases in Women With Newly Diagnosed Ovarian Cancer.

Aim: The purpose of this study was to analyze the incidence, clinical characteristics, prognostic factors and survival of ovarian cancer patients with liver metastases upon initial diagnosis. Methods: Patients with ovarian cancer liver metastases upon initial diagnosis between 2010 and 2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate logistic regression was performed to identify the predictors of the presence of liver metastases in newly diagnosed ovarian cancer patients. Overall survival (OS) was assessed using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression was conducted to determine the independent prognostic factors for OS. Results: A total of 1,744 ovarian cancer patients with liver metastases was identified from the SEER database, accounting for 6.7% of the entire ovarian cancer patients. As to the unique distant organ provided by SEER, liver was the most common metastatic site of ovarian cancer (4.65%). Age, race, laterality, histology, pathological grade, extrahepatic sites, stage of tumor were the predictors of the presence with liver metastases revealed by multivariable logistic regression model. Median OS for the patients with liver metastases at initial diagnosis of ovarian cancer was 16.0 months. Multivariate Cox regression model confirmed race, histology, extrahepatic metastatic sites, surgery and marital status were independent prognostic factors for OS. Conclusion: The study provided population-based estimates of the incidence and prognosis of newly diagnosed ovary cancer patients with liver metastases, which could be potentially used for the risk assessment and individualized treatment.

Circ0004390 promotes cell proliferation through sponging miR-198 in ovarian cancer.

Circular RNAs (circRNAs) are a novel class of non-coding RNAs which play important roles in human diseases and tumor progression. However, the function of circRNAs in ovarian cancer remains to be uncovered. Here we found a large amount of circRNAs that are differentially expressed in ovarian cancer tissues compared with normal ovarian tissues. We further identified one circRNA derived from the LPAR3 gene and termed Circ0004390, which was frequently upregulated in ovarian cancer tissues. The knockdown of Circ0004390 can significantly reduce the proliferation of ovarian cancer cells. We further demonstrated that Circ0004390 may promote cell proliferation by acting as a sponge for the miR-198 family to regulated the MET expression in ovarian cancer cells. The level of Circ0004390 was closely related with overall survival of ovarian cancer patients. Our findings suggested that Circ0004390 regulated ovarian cancer proliferation by miR-198/MET axis, which might provide a potential target for the treatment of ovarian cancer.

Heterogeneous survival between stage IIA and stage IIIA colon cancer when different numbers of lymph nodes are harvested.

BACKGROUND: We aim to compare the prognosis between patients with stage IIA and stage IIIA colon cancer. METHODS: We analysed patients with stage IIA or stage IIIA colon cancer based on data from the US Surveillance, Epidemiology, and End Results (SEER) database. Survival data were generated as Kaplan-Meier curves and were compared by log-rank tests. A multivariate Cox proportional hazards model was used to analyze the risk factors. RESULTS: In total, 43 379 patients (38 784 stage IIA and 4595 stage IIIA) were included from the SEER database. A Kaplan-Meier analysis showed no significant difference between patients with stage IIA and IIIA colon cancer (P = 0.547). In the subgroup of patients with number of lymph nodes harvested (LNH) ≥12, a multivariate analysis showed that compared with stage IIA patients, stage IIIA patients were more likely to have a poorer cancer-specific survival (CSS) (hazard ratio (HR) 1.252, 95% confidence interval (CI) 1.095-1.431, P = 0.001). In the subgroup of patients with LNH <12, a multivariate analysis showed that compared with stage IIA patients, stage IIIA patients were more likely to have a better CSS (HR 0.820, 95% CI 0.731-0.919, P = 0.001). CONCLUSIONS: Patients with stage IIA colon cancer had a CSS comparable with that of patients with stage IIIA disease. When adequate lymph nodes were retrieved (LNH ≥12), stage IIA patients had a greater CSS than stage IIIA patients. On the contrary, when inadequate lymph nodes were retrieved (LNH <12), stage IIA patients had a poorer CSS than stage IIIA patients.

The association between small tumor size and poor survival in T4 mucinous adenocarcinoma of colon without distant metastasis.

PURPOSE: The purpose of this study was to analyze the impact of tumor size on cancer-specific survival (CSS) in patients with mucinous adenocarcinoma (MAC) of the colon, showing heavy intestinal wall invasion without distant metastasis (T4 N0-2 M0). METHODS: Patients with T4N0-2M0 MAC of colon were analyzed based on data from the US Surveillance, Epidemiology, and End Results (SEER) database. Survival was analyzed using the Kaplan-Meier method, and the log-rank test was used to identify differences. Risk factors were analyzed using the Cox proportional hazard model. A preliminary analysis of T4N0-2M0 adenocarcinoma of colon patients from the SEER database is also presented. RESULTS: A total of 585 patients from the SEER database were included in the analysis. The cutoff value (5.0 cm) was determined using the X-tile program. Kaplan-Meier analysis showed that tumors ≤5.0 cm had a poorer CSS compared to tumors >5.0 cm (p=0.034). Multivariate analysis indicated that tumor size is an independent prognostic factor for these patients, and compared to tumors ≤5.0 cm, tumors >5.0 cm were more likely to have better CSS (HR 0.658, 95% CI 0.506-0.854, p=0.002). Tumor size was also analyzed as a continuous variable in multivariate analysis, and CSS decreased with decreasing tumor size (HR 0.919, 95% CI 0.873-0.968, p<0.001). No significant association between tumor size and CSS was observed in patients with T4N0- 2M0 MAC of the colon. CONCLUSION: Smaller tumor size is associated with poorer CSS in patients with T4N0-2M0 MAC of the colon.

LODDS is superior to lymph node ratio for the prognosis of node-positive rectal cancer patients treated with preoperative radiotherapy.

PURPOSE: Yielding pathologic-lymph node ratio (yp-LNR) was considered to be a better staging system than yp-N stage in rectal cancer patients treated with preoperative radiotherapy (pre-RT). We aimed to compare the predictive ability of yielding pathologic log odds of positive lymph nodes (yp-LODDS) with that of yp-LNR for cancer-specific survival (CSS) in stage III rectal cancer patients treated with pre-RT. METHODS: We analyzed stage III rectal cancer patients treated with pre-RT in the Surveillance, Epidemiology and End Results (SEER) database. Patients were classified into 4 groups, yp-LNR1 to 4, based on the LNR cutoff points 0.25, 0.50, and 0.75. Subjects were categorized into 5 groups, yp-LODDS1 to yp-LODDS5, based on the LODDS cutoff points -1, 0, 1, and 2. Univariate and multivariate Cox proportional hazards models were performed to analyze the risk factors for survival outcome. RESULTS: A total of 4,612 patients were included from the SEER database. Patients in the yp-LNR4 group could be further divided into yp-LODDS4 and yp-LODDS5 groups with 5-year CSS of 47.6% and 31.5%, respectively (p<0.001). In the multivariate analysis without yp-LODDS, yp-LNR was an independent prognostic factor (hazard ratio [HR] 2.006, 95% confidence interval [CI] 1.619-2.484, p<0.001). However, after adjusting for yp-LODDS, yp-LNR was no longer associated with CSS (p = 0.393), and yp-LODDS was identified as an independent prognostic factor (HR 1.274, 95% CI 1.069-1.520, p = 0.007). CONCLUSIONS: The prognostic value of yp-LNR can be confounded by yp-LODDS. In stage III rectal cancer patients treated with pre-RT, yp-LODDS has superior discrimination power over yp-LNR and can more accurately evaluate CSS.

Younger Age Is Associated with Poorer Survival in Patients with Signet-Ring Cell Carcinoma of the Colon without Distant Metastasis.

Background. In general, younger age is associated with better survival in patients with colon cancer. In this study, we aim to analyze the impact of age on cancer-specific survival (CSS) in patients with signet-ring cell carcinoma (SRCC) of the colon, a particularly aggressive type of colon cancer. Methods. Information on patients with SRCC of the colon with no distant metastasis was extracted from the US Surveillance, Epidemiology, and End Results (SEER) database. An X-tile plot was used to determine the optimal cutoff age at diagnosis. Results. A total of 776 patients were included in data analysis. The X-tile program revealed an optimal cutoff at 35 years of age. A higher percentage of stage III disease and a higher percentage of N2 disease were observed in patients ≤ 35 years of age. The multivariate Cox proportional model demonstrated that patients ≤ 35 years of age were more likely to have a poorer survival outcome compared with patients aged >35 years (HR 1.411, 95% CI 1.032-1.929, and P = 0.031). Conclusion. In contrast to the association of younger age with better survival in colon cancer patients, younger age (≤35 years) is associated with poorer survival outcome in patients with SRCC of the colon without distant metastasis.

Log odds of positive lymph nodes is a superior prognostic indicator in stage III rectal cancer patients: A retrospective analysis of 17,632 patients in the SEER database.

BACKGROUND: Lymph node ratio (LNR) is considered a better staging system than N stage in rectal cancer. More recently, log odds of positive lymph nodes (LODDS) was identified as a novel prognostic classifier in many malignancies. Accordingly, our study aims to compare the predictive ability of LODDS with LNR for cancer-specific survival (CSS) in patients with stage III rectal cancer. METHODS: We analyzed a subpopulation of the Surveillance, Epidemiology and End Results (SEER) database containing patients with stage III rectal cancer. The patients were categorized into four groups (LNR1 to 4) according to the LNR cut-off values 0.25, 0.50 and 0.75. The patients were divided into five groups (LODDS1 to LODDS5) according to the LODDS cut-off values of LODDS -1, 0, 1 and 2. Univariate and multivariate analyses using the Cox proportional hazards model were performed to analyze the risk factors for survival outcome. RESULTS: A total of 17,632 patients were included from the SEER database. Patients with LNR4 could be further divided into LODDS4 and LODDS5 and had a 5-year CSS of 39.1% and 23.3%, respectively (p < 0.001). A multivariate analysis without the inclusion of LODDS showed that the LNR was an independent prognostic factor (HR 2.254, 95% confidence interval (CI) 2.034-2.497, p < 0.001). However, after adjusting for LODDS, the LNR was no longer associated with CSS (HR 0.709, 95% CI 0.481-1.045, p = 0.083), and LODDS was identified as an independent prognostic factor (HR 1.303, 95% CI 1.197-1.419, p < 0.001). CONCLUSION: The prognostic value of LNR can be confounded by LODDS. In stage III rectal cancer patients, LODDS has superior discrimination power over LNR and can more accurately evaluate CSS.