Epithelial Ovarian Cancer (EOC) is the fifth leading cause of cancer-related deaths in women in the USA, gets diagnosed at an advanced stage (stage III-IV) with local or distant metastasis. The primary therapeutic regimen of EOC involves surgical removal of all the visible tumor mass followed by platinum-based chemotherapy either as a single agent or in combination with a taxane. Despite initial responses, over 70% of EOC patients develop recurrent disease and they are often resistant to available chemotherapeutic drugs, contributing to poor survival. This appalling situation emphasizes the critical need to identify the molecular mechanisms involving recurrence of these tumors' aggressive growth and developing therapeutic resistance. Our analysis from chemo naïve and recurrent tumors from the same patients' samples, and isogenic ovarian cancer cell lines data showed recurrent tumors and resistant cell lines several upregulated cancer stem cell markers including ALDH1A1, SOX2 and altered expression of DNA damage response and repair genes that are involved in the processing of platinum adducts and crosslink repair. Prominently, RAD6, an E2ubiquitin-conjugating enzyme, is significantly (> 6 folds) overexpressed in recurrent ovarian tumors and associated with aggressive tumor cell growth, stemness, chemoresistance to platinum drugs, and poor prognosis. Our studies validated that, chemotherapy induced upregulated RAD6 reprograms epigenetic milieu in tumor cells through ubiquitination of histone variants H2A, H2AX, and H2B, which further recruits additional epigenetic modifiers to these regions and regulates genes involved in DNArepair, cell survival, stemness, and chemoresistance. Additionally, our mechanistic studies demonstrate RAD6 dependent recruitment of several epigenetic modifiers such as histone methylases and demethylases to regions of ubiquitylated histones and their crosstalk. Collectively, our study presents novel chemotherapy induced epigenetic modulator contributing to therapeutic recurrence of EOC and could be an important therapeutic target to treat chemo-resistant EOC and improve the progression-free survival of patients suffering from this deadly disease. Formatted: Right, Indent: Left: 1" Citation Format: Tasmin Rahman Omy, Shirisha Jonnalagadda, Mark Reedy, Komaraiah Palle. RAD6-mediated epigenetic reprogramming contributes to therapy-induced chemo-resistance in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2111.
Approximately 90% of ovarian cancer (OC) is Epithelial ovarian Cancer (EOC) subtype and claims ~15,000 lives in the United States annually, making it the deadliest reproductive cancer in women. There are few treatment options for EOC, amongst them include surgical resection of tumors or debulking, and chemotherapy alone or combination. In general, the survival rate of patients with EOC is about 48% and this has not changed in last few decades. According to recent reports from American Cancer Society and SEER, racial disparity in ovarian cancer not only exists for African American (AA) patients, but is worsening over the past few years. African American (AA) patients presents with more advanced disease and develop chemoresistance frequently, and as such, they experience worse survival. Thus identifying the cause of this discrepancy, or more importantly, describing which AA patients are at the highest risk of therapeutic relapse would alter our current treatment strategies and improve overall disease free survival rate. Therefore, the central focus of this proposal is to delineate the molecular and genetic mechanisms contributing to racial disparity of AA patients. Therefore, the overall objective of our studies are to identify the etiology of racial disparity in ovarian cancer and define the molecular networks that contribute this discrepancy in outcomes. Lymphoblastic Leukemia-Derived Sequence 1 (LYL1) is a polypeptide that harbors basic helix-loop-helix transcription factor, a DNA binding motif and dysregulated in many cancers including EOC. Analysis of TCGA data for EOC revealed that LYL1 gene amplification in about 12% patients and associated with poor prognosis. Interestingly, further analysis of LYL1 copy number alteration in different ethnicities disclosed LYL1 amplification in about 36% of the African American (AA) EOC patients. Importantly, EOC patients with low LYL1 (n=1640) expression has better survival probability compared to patients with overexpressed LYL1 (n=202). This discrepancy in survival probability is much more prominent in AA EOC patients. As this is an intriguing observation, we evaluated the levels of LYL1 expression in different EOC cell lines in comparison with fallopian tube epithelial cells. Our data shows, upregulation of LYL1 in most of the EOC cell lines compared to normal fallopian tube epithelial cells. To examine the upregulated LYL1 in EOC cell lines, we performed siRNA mediated downregulation, and evaluated their clonogenic, migration invasion potential. Consistent with the TCGA data, knocking down LYL1 in EOC cells significantly attenuated their clongenic, migration and invasion potential. Furthermore, ectopic overexpression of LYL1 in EOC cells that shows deep deletion of the gene, exhibited increased clonogenicity, invasion and migration. Collectively, our studies indicate an important role for LYL1 in EOC tumor progression and metastatic phenotypes, and could be a biomarker for disparities in EOC outcomes. Citation Format: Damieanus Ochola, Shirisha Jonnalagadda, Swetha Peddibhotla, Tasmin Omy, Mark Reedy, Palle Komaraiah. Upregulated LYL1 promotes epithelial ovarian cancer (EOC) cell growth and metastasis [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-132.
Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy. This cancer typically is not detected, 70-80% of patients, until an advanced stage (stage III-IV). The standard of care OC entails complete surgical resection of all visible abdominal-pelvic tumors, followed by platinum-based chemotherapy combined with a taxane. New recommendations for patients responding to adjuvant therapy is to include a PARP inhibitor with or without bevacizumab for maintenance therapy. Despite initial responses, the majority of stage 3 & 4 more than 70% of OC patients experience recurrent disease. Frequently, individuals become resistant to these treatments. This dreadful circumstance highlights the pressing need to identify the molecular mechanisms underlying the disease's aggressive nature upon recurrence and the development of treatment resistance. Several genetic and epigenetic factors have been linked to the reprogramming of tumor cells by controlling the pattern of transcriptional and post-transcriptional gene expression. Particularly, the miRNA-mediated regulatory circuit plays a significant role in tumor progression and therapeutic responses. Our analysis of miRNA expression signature in human ovarian cancer cell line panel showed little to no expression of miR221_5p and a corresponding increase in DNA damage response and repair gene RAD18 expression. RAD18 plays a critical role in cellular DNA damage tolerance and repair activity against chemotherapeutics, including platinum drugs. Similarly, loss of miRNA221_5p is associated with aggressive tumor cell growth, stemness, chemoresistance to platinum drugs, and poor prognosis in several cancers. Based on this information, we have hypothesized that miR221_5p regulates RAD18-mediated DNA damage tolerance and repair and may offer novel therapeutic intervention to overcome EOC chemoresistance. Our experimental data confers that miR221_5p post-transcriptionally regulates RAD18 by binding to its 3’-UTR region and restores OC cell sensitivity to platinum drugs. Mechanistically, our results demonstrate that miRNA221_5p epigenetically regulates RAD18-mediated DNA damage tolerance and homologous recombination repair and could be a novel therapeutic to overcome OC chemoresistance. Collectively, our studies identify a novel chemotherapy-induced epigenetic modulator in OC therapeutic resistance and offer novel miRNA 221-5p-mediated therapeutic intervention for the treatment of chemoresistant OC and to prevent disease recurrence. Citation Format: Tasmin Rahman Omy, Chinnadurai Mani, Komaraiah Palle, Mark Reedy. Epigenetic-miRNA regulatory circuit confers ovarian cancer chemoresistance through RAD18-mediated DNA damage tolerance and repair signaling. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6106.
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