title: Inhibitor of differentiation 4 (ID4) inactivation promotes de novo steroidogenesis and castration-resistant prostate cancer.
abstract: Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the Western world. The transition of androgen-dependent PCa to castration-resistant (CRPC) is a major clinical manifestation during disease progression and presents a therapeutic challenge. Our studies have shown that genetic ablation of inhibitor of differentiation 4 (Id4), a dominant-negative helix loop helix protein, in mice results in prostatic intraepithelial neoplasia lesions and decreased Nkx3.1 expression without the loss of androgen receptor (Ar) expression. ID4 is also epigenetically silenced in the majority of PCa. However, the clinical relevance and molecular pathways altered by ID4 inactivation in PCa are not known. This study investigates the effect of loss of ID4 in PCa cell lines on tumorigenicity and addresses the underlying mechanism. Stable silencing of ID4 in LNCaP cells (L-ID4) resulted in increased proliferation, migration, invasion, and anchorage-independent growth. An increase in the rate of tumor growth, weight, and volume was observed in L-ID4 xenografts compared with that in the LNCaP cells transfected with nonspecific short hairpin RNA (L+ns) in noncastrated mice. Interestingly, tumors were also observed in castrated mice, suggesting that loss of ID4 promotes CRPC. RNA sequence analysis revealed a gene signature mimicking that of constitutively active AR in L-ID4, which was consistent with gain of de novo steroidogenesis. Prostate-specific antigen expression as a result of persistent AR activation was observed in L-ID4 cells but not in L+ns cells. The results demonstrate that ID4 acts as a tumor suppressor in PCa, and its loss, frequently observed in PCa, promotes CRPC through constitutive AR activation.
authors.affiliation: Center for Cancer Research and Therapeutic Development (D.P., A.E.K., P.S., J.J., S.G., S.C., P.N., N.J.B., J.C.), Clark Atlanta University, Atlanta, Georgia 30314; and College of Pharmacy (M.K.-Y., R.P.), Mercer University, Atlanta, Georgia 30341.
authors.forename: Divya
authors.initials: D
authors.lastname: Patel
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Knowell
authors.forename: Maxwell
authors.initials: M
authors.lastname: Korang-Yeboah
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sharma
authors.forename: Jugal
authors.initials: J
authors.lastname: Joshi
authors.forename: Shanora
authors.initials: S
authors.lastname: Glymph
authors.forename: Swathi
authors.initials: S
authors.lastname: Chinaranagari
authors.forename: Peri
authors.initials: P
authors.lastname: Nagappan
authors.forename: Ravi
authors.initials: R
authors.lastname: Palaniappan
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Bowen
authors.forename: Jaideep
authors.initials: J
authors.lastname: Chaudhary
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018572:Disease-Free Survival; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000502:physiology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D013739:Testosterone / Q000096:biosynthesis*; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000502:physiology
chemical_list: C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; D025521:Tumor Suppressor Proteins; D013739:Testosterone