EZH2 Promotes E2F-Driven SCLC Tumorigenesis through Modulation of Apoptosis and Cell-Cycle Regulation Roland Hubaux, PhD, Kelsie L. Thu, BSc, Bradley.

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EZH2 Promotes E2F-Driven SCLC Tumorigenesis through Modulation of Apoptosis and Cell-Cycle Regulation Roland Hubaux, PhD, Kelsie L. Thu, BSc, Bradley P. Coe, PhD, Calum MacAulay, PhD, Stephen Lam, MD, Wan L. Lam, PhD Journal of Thoracic Oncology Volume 8, Issue 8, Pages 1102-1106 (August 2013) DOI: 10.1097/JTO.0b013e318298762f Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Knockdown of EZH2 up-regulates proapoptotic factors and the cell-cycle inhibitor, p21. Immunoblotting was used to determine the relative expression levels of p21 and multiple proteins of the B-cell lymphoma 2 (BCL-2) family involved in the activation of apoptosis in EZH2 knockdown and control (PLKO) small-cell lung cancer cells. GAPDH was used as a loading control. EZH2, enhancer of zeste homolog 2; GAPHD, glyceraldehyde 3-phosphate dehydrogenase. Journal of Thoracic Oncology 2013 8, 1102-1106DOI: (10.1097/JTO.0b013e318298762f) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 EZH2 knockdown reduces SCLC viability.The MTT assay was used to compare cell viability in EZH2 knockdown (shEZH2) and corresponding control (PLKO) SCLC cells. Assays were performed on exponentially growing cells measured over 5 consecutive days. Results plotted are background subtracted mean ± standard deviation absorbance values for triplicate wells of a representative experiment. Experiments were repeated twice. Asterisks indicate statistically significant differences in viability on day 5 (*p < 0.05; ***p < 0.001) as determined using a Student’s t test. EZH2, enhancer of zeste homolog 2; shEZH2, short hairpin enhancer of zeste homolog 2; SCLC, small-cell lung cancer; OD, optical density. Journal of Thoracic Oncology 2013 8, 1102-1106DOI: (10.1097/JTO.0b013e318298762f) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Apoptotic rates are elevated on EZH2 inhibition. Levels of apoptosis for EZH2 knockdown and control small-cell lung cancer cells were obtained by flow cytometry after ethanol fixation and propidium iodide incorporation. Cells in the sub-G0/1 phase (characterized by low DNA content because of loss of fragmented DNA caused by ethanol permeabilization), which were also within the gate for viable cells (forward vs. side scatter dot plot) were considered apoptotic. Results plotted are mean + standard deviation of the percentage of viable cells that were apoptotic from three independent experiments. Student’s t tests were used to compare EZH2 knockdown cells with respective PLKO controls. Asterisks indicate statistically significant differences (*p < 0.05; ***p < 0.001). EZH2, enhancer of zeste homolog 2; shEZH2, short hairpin enhancer of zeste homolog 2. Journal of Thoracic Oncology 2013 8, 1102-1106DOI: (10.1097/JTO.0b013e318298762f) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 The postulated role of EZH2 in SCLC biology. The RB1/E2F pathway is disrupted in the vast majority of SCLCs through RB1 inactivation or E2F copy number gains. The model illustrated summarizes the different activities of E2F factors that have been described in cancer and the particular role of EZH2 that we have discovered in SCLC (circled). Besides activation of the usual cell-cycle factors required for cell-cycle progression, such as cyclins A and E; p107; dihydrofolate reductase; thymidine kinase; thymidylate synthetase; PCNA; or DNA polymerase α, E2F overactivation can also lead to inhibition of the cell cycle in specific scenarios through induction of p21 and activation of apoptosis. EZH2 plays an essential role in SCLC by favoring the oncogenic processes of the RB1/E2F pathway in SCLC. Specifically, EZH2 negatively regulates the expression of the proapoptotic factors, Puma and Bad, as well as the cell-cycle inhibitor, p21, thereby promoting SCLC tumorigenicity. Given the functions of EZH2 in SCLC biology, our findings suggest that it is a promising therapeutic target for this cancer type. EZH2, enhancer of zeste homolog 2; RB1, retinoblastoma protein; SCLC; small-cell lung cancer; PCNA, proliferating cell nuclear antigen; DHFR, dihydroolate reductase; CDK, cyclin-dependent kinases; TS, thymidylate synthetase. Journal of Thoracic Oncology 2013 8, 1102-1106DOI: (10.1097/JTO.0b013e318298762f) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions