First name
Seyed Amir
Last name
Hosseini
Year of Study
Research Center
Thesis Title
Dissecting the role of lysine-specific demethylase1 (LSD1): identification of markers/effectors of sensitivity to LSD1 inhibitors in cancer
Thesis Abstract
LSD1 is a flavin-containing amine oxidase that, by reducing the cofactor FAD, demethylates
H3K4me1/2 and H3K9me1/2 at target loci in a context-dependent manner. LSD1 could be an
attractive target for cancer therapy because of its deregulation in a number of cancers, including
lung, breast, melanoma and hematological malignancies. Given the unsatisfactory clinical
outcome associated with standard chemotherapy in acute myeloid leukemia (AML) and melanoma
treatment, there is an essential need for new targets. Recently LSD1 have gained great interest for
their use as anticancer therapeutics. However, the efficacy of LSD1 inhibitors is limited to a
substantial subset of cancer cells. Thus, identification of good predictive biomarkers for sensitivity
to treatment with LSD1 inhibitors will be of great value in determining the most suitable
therapeutic setting.
In this study we demonstrated that, LSD1 drives unrestricted cycling of cancer cells by directing
repressing CDKN1A (p21) gene, which allows unrestricted G1-S transition. Inhibition of LSD1
suppresses G1 to S phase transition and cell proliferation in a p21-dependent manner and P21
provoked by LSD1 inhibitor could serves as a biomarker to verify pharmacological activity and a
prognostic tool reflecting responsiveness to LSD1 inhibitors. Moreover, loss of p21 enables
progression of cell cycle and rescues the LSD1 inhibitor phenotypes. Finally, we found that forced
cell cycle inhibition either with p21 induction by HDAC inhibitors or directly by CDK inhibitors
H3K4me1/2 and H3K9me1/2 at target loci in a context-dependent manner. LSD1 could be an
attractive target for cancer therapy because of its deregulation in a number of cancers, including
lung, breast, melanoma and hematological malignancies. Given the unsatisfactory clinical
outcome associated with standard chemotherapy in acute myeloid leukemia (AML) and melanoma
treatment, there is an essential need for new targets. Recently LSD1 have gained great interest for
their use as anticancer therapeutics. However, the efficacy of LSD1 inhibitors is limited to a
substantial subset of cancer cells. Thus, identification of good predictive biomarkers for sensitivity
to treatment with LSD1 inhibitors will be of great value in determining the most suitable
therapeutic setting.
In this study we demonstrated that, LSD1 drives unrestricted cycling of cancer cells by directing
repressing CDKN1A (p21) gene, which allows unrestricted G1-S transition. Inhibition of LSD1
suppresses G1 to S phase transition and cell proliferation in a p21-dependent manner and P21
provoked by LSD1 inhibitor could serves as a biomarker to verify pharmacological activity and a
prognostic tool reflecting responsiveness to LSD1 inhibitors. Moreover, loss of p21 enables
progression of cell cycle and rescues the LSD1 inhibitor phenotypes. Finally, we found that forced
cell cycle inhibition either with p21 induction by HDAC inhibitors or directly by CDK inhibitors
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