Data from Identification of Genes Required for Enzalutamide Resistance in Castration-Resistant Prostate Cancer Cells <i>In Vitro</i>

Abstract

<div>Abstract<p>Castration-resistant prostate cancer can be treated with the antiandrogen enzalutamide, but responses and duration of response are variable. To identify genes that support enzalutamide resistance, we performed a short hairpin RNA (shRNA) screen in the bone-homing, castration-resistant prostate cancer cell line, C4-2B. We identified 11 genes (<i>TFAP2C, CAD, SPDEF, EIF6, GABRG2, CDC37, PSMD12, COL5A2, AR, MAP3K11,</i> and <i>ACAT1</i>) whose loss resulted in decreased cell survival in response to enzalutamide. To validate our screen, we performed transient knockdowns in C4-2B and 22Rv1 cells and evaluated cell survival in response to enzalutamide. Through these studies, we validated three genes (<i>ACAT1, MAP3K11,</i> and <i>PSMD12</i>) as supporters of enzalutamide resistance <i>in vitro</i>. Although <i>ACAT1</i> expression is lower in metastatic castration-resistant prostate cancer samples versus primary prostate cancer samples, knockdown of <i>ACAT1</i> was sufficient to reduce cell survival in C4-2B and 22Rv1 cells. <i>MAP3K11</i> expression increases with Gleason grade, and the highest expression is observed in metastatic castration-resistant disease. Knockdown of <i>MAP3K11</i> reduced cell survival, and pharmacologic inhibition of MAP3K11 with CEP-1347 in combination with enzalutamide resulted in a dramatic increase in cell death. This was associated with decreased phosphorylation of AR-Serine650, which is required for maximal AR activation. Finally, although <i>PSMD12</i> expression did not change during disease progression, knockdown of <i>PSMD12</i> resulted in decreased AR and AR splice variant expression, likely contributing to the C4-2B and 22Rv1 decrease in cell survival. Our study has therefore identified at least three new supporters of enzalutamide resistance in castration-resistant prostate cancer cells <i>in vitro</i>.</p></div>