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000170397 1001_ $$aKalogirou, C.$$b0
000170397 245__ $$aMiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer.
000170397 260__ $$a[London]$$bNature Publishing Group UK$$c2021
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000170397 520__ $$aProstate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa.
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000170397 7001_ $$aLinxweiler, J.$$b1
000170397 7001_ $$00000-0002-3487-0560$$aSchmucker, P.$$b2
000170397 7001_ $$0P:(DE-He78)7b7131e0870c28d432e48873d295460f$$aSnaebjornsson, M. T.$$b3$$udkfz
000170397 7001_ $$00000-0003-0485-7303$$aSchmitz, W.$$b4
000170397 7001_ $$aWach, S.$$b5
000170397 7001_ $$aKrebs, M.$$b6
000170397 7001_ $$aHartmann, E.$$b7
000170397 7001_ $$aPuhr, M.$$b8
000170397 7001_ $$aMüller, A.$$b9
000170397 7001_ $$aSpahn, M.$$b10
000170397 7001_ $$aSeitz, A. K.$$b11
000170397 7001_ $$aFrank, T.$$b12
000170397 7001_ $$aMarouf, H.$$b13
000170397 7001_ $$00000-0001-7070-7341$$aBüchel, G.$$b14
000170397 7001_ $$aEckstein, M.$$b15
000170397 7001_ $$aKübler, H.$$b16
000170397 7001_ $$00000-0002-0376-6533$$aEilers, M.$$b17
000170397 7001_ $$aSaar, M.$$b18
000170397 7001_ $$aJunker, K.$$b19
000170397 7001_ $$aRöhrig, F.$$b20
000170397 7001_ $$aKneitz, B.$$b21
000170397 7001_ $$00000-0001-7650-8458$$aRosenfeldt, M. T.$$b22
000170397 7001_ $$0P:(DE-He78)94ae391f53fb9285e1b68f9930615af1$$aSchulze, Almut$$b23$$eLast author$$udkfz
000170397 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-021-25325-9$$gVol. 12, no. 1, p. 5066$$n1$$p5066$$tNature Communications$$v12$$x2041-1723$$y2021
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