{"id":{"repo_id":"buffalo","oai_identifier":"oai:ubir.buffalo.edu:10477/78412"},"canonical_url":"https://search.dev.ndltd.org/etd/buffalo/oai:ubir.buffalo.edu:10477/78412","repository":{"repo_id":"buffalo","name":"Buffalo","base_url":"https://ubir.buffalo.edu/oai/request"},"display":{"title":"Lysine-specific histone demethylase 1A as a regulator of reactive oxygen species response in cancer therapy","abstract":"Ph.D.","abstract_html":"Ph.D.","abstract_has_math":false,"creators":["Mudambi, Shaila; 0000-0003-1233-8861"],"institution":"State University of New York at Buffalo","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Paragh, Gyorgy","Roswell Park"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-10-24T20:44:37Z","date_published":"2018-10-24T20:44:37Z","updated_at":"2026-07-27T19:05:09Z","subjects":["biochemistry","biophysics"],"languages":["eng"],"rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10477/78412","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Paragh, Gyorgy","Roswell Park"]},{"key":"dc:creator","label":"Author","values":["Mudambi, Shaila; 0000-0003-1233-8861"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2018-10-24T20:44:37Z","2018","2018-07-27 11:50:34"]},{"key":"dc:publisher","label":"Institution","values":["State University of New York at Buffalo"]},{"key":"dc:type","label":"Dc Type","values":["Text","Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["biochemistry","biophysics"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/10477/78412"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Ph.D.","Lysine Specific Demethylase 1 (KDM1A / LSD1) is a ubiquitously expressed transcriptional co-regulator known to direct both cell growth and differentiation in multiple cell types. High expression of KDM1A in many cancers, including esophageal squamous cell carcinomas (SCC) and rhabdomyosarcoma has been linked to poor prognosis and decreased survival. KDM1A regulates mitochondrial respiration which is the primary reactive oxygen species (ROS) generator in the cell. KDM1A also stabilizes HIF-1A (hypoxia inducible factor 1A) which maintains ROS levels in cells by increasing glucose uptake, glycolysis and levels of endogenous antioxidants. To date, the role of KDM1A in regulation of cellular ROS response in cancer is unknown. Cancer cells rely on maintaining the redox balance to survive and oxidative stress is used clinically to selectively eliminate cancer cells. In our current work we aimed to explore the role of KDM1A in regulation of the ROS response and the utility of KDM1A inhibitors in combination with ROS inducing cancer therapies. In vitro experiments assessing cell viability, flow cytometry-based ROS measurement and seahorse assay to assess mitochondrial respiration were carried out on HaCaT, immortalized keratinocytes and FaDu, head and neck cancer cells and other in vitro models. To understand the role of KDM1A in ROS response we used inhibitors of KDM1A activity and modified cellular expression of KDM1A and some of its interacting partners in our models. We also assess expression of ROS responsive genes. Our results show that KDM1A inhibition sensitized cells to oxidative stress accompanied by an increase in total cellular ROS which was mitigated by treatment with the antioxidant, N-acetyl cysteine. KDM1A inhibition decreased basal mitochondrial respiration as well as the induction of HIF-1A after ROS exposure. Overexpression of HIF-1A salvaged cells from KDM1A inhibition enhanced sensitivity to ROS. Increased sensitivity of ROS after KDM1A inhibition was determined to be mediated by HIF-1A and depletion of endogenous glutathione. We also show that treatment with KDM1A specific inhibitor bizine enhanced the efficacy of buthionine sulfoximine, auranofin and photodynamic therapy (PDT), cancer therapies known to increase ROS. Hence, we establish a novel mechanism for KDM1A in regulating ROS response via HIF-1A in cancer and provide an innovative use for KDM1A inhibitors in enhancing the efficacy of ROS inducing chemotherapies."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Lysine-specific histone demethylase 1A as a regulator of reactive oxygen species response in cancer therapy"]}]}],"canonical_facts":{"dc:contributor":["Paragh, Gyorgy","Roswell Park"],"dc:creator":["Mudambi, Shaila; 0000-0003-1233-8861"],"dc:date":["2018-10-24T20:44:37Z","2018","2018-07-27 11:50:34"],"dc:description":["Ph.D.","Lysine Specific Demethylase 1 (KDM1A / LSD1) is a ubiquitously expressed transcriptional co-regulator known to direct both cell growth and differentiation in multiple cell types. High expression of KDM1A in many cancers, including esophageal squamous cell carcinomas (SCC) and rhabdomyosarcoma has been linked to poor prognosis and decreased survival. KDM1A regulates mitochondrial respiration which is the primary reactive oxygen species (ROS) generator in the cell. KDM1A also stabilizes HIF-1A (hypoxia inducible factor 1A) which maintains ROS levels in cells by increasing glucose uptake, glycolysis and levels of endogenous antioxidants. To date, the role of KDM1A in regulation of cellular ROS response in cancer is unknown. Cancer cells rely on maintaining the redox balance to survive and oxidative stress is used clinically to selectively eliminate cancer cells. In our current work we aimed to explore the role of KDM1A in regulation of the ROS response and the utility of KDM1A inhibitors in combination with ROS inducing cancer therapies. In vitro experiments assessing cell viability, flow cytometry-based ROS measurement and seahorse assay to assess mitochondrial respiration were carried out on HaCaT, immortalized keratinocytes and FaDu, head and neck cancer cells and other in vitro models. To understand the role of KDM1A in ROS response we used inhibitors of KDM1A activity and modified cellular expression of KDM1A and some of its interacting partners in our models. We also assess expression of ROS responsive genes. Our results show that KDM1A inhibition sensitized cells to oxidative stress accompanied by an increase in total cellular ROS which was mitigated by treatment with the antioxidant, N-acetyl cysteine. KDM1A inhibition decreased basal mitochondrial respiration as well as the induction of HIF-1A after ROS exposure. Overexpression of HIF-1A salvaged cells from KDM1A inhibition enhanced sensitivity to ROS. Increased sensitivity of ROS after KDM1A inhibition was determined to be mediated by HIF-1A and depletion of endogenous glutathione. We also show that treatment with KDM1A specific inhibitor bizine enhanced the efficacy of buthionine sulfoximine, auranofin and photodynamic therapy (PDT), cancer therapies known to increase ROS. Hence, we establish a novel mechanism for KDM1A in regulating ROS response via HIF-1A in cancer and provide an innovative use for KDM1A inhibitors in enhancing the efficacy of ROS inducing chemotherapies."],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/10477/78412"],"dc:language":["eng"],"dc:publisher":["State University of New York at Buffalo"],"dc:rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"dc:subject":["biochemistry","biophysics"],"dc:title":["Lysine-specific histone demethylase 1A as a regulator of reactive oxygen species response in cancer therapy"],"dc:type":["Text","Dissertation"]},"updated_at":"2026-07-27T19:05:09Z"}