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C-MYC-induced sebaceous gland differentiation is controlled by an androgen receptor/p53 axis.

ABSTRACT: Although the sebaceous gland (SG) plays an important role in skin function, the mechanisms regulating SG differentiation and carcinoma formation are poorly understood. We previously reported that c-MYC overexpression stimulates SG differentiation. We now demonstrate roles for the androgen receptor (AR) and p53. MYC-induced SG differentiation was reduced in mice lacking a functional AR. High levels of MYC triggered a p53-dependent DNA damage response, leading to accumulation of proliferative SG progenitors and inhibition of AR signaling. Conversely, testosterone treatment or p53 deletion activated AR signaling and restored MYC-induced differentiation. Poorly differentiated human sebaceous carcinomas exhibited high p53 and low AR expression. Thus, the consequences of overactivating MYC in the SG depend on whether AR or p53 is activated, as they form a regulatory axis controlling proliferation and differentiation.

SUBMITTER: Cottle DL

PROVIDER: S-EPMC3778892 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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c-MYC-induced sebaceous gland differentiation is controlled by an androgen receptor/p53 axis.

Cottle Denny L DL Kretzschmar Kai K Schweiger Pawel J PJ Quist Sven R SR Gollnick Harald P HP Natsuga Ken K Aoyagi Satoru S Watt Fiona M FM

Cell reports 20130209 2

Although the sebaceous gland (SG) plays an important role in skin function, the mechanisms regulating SG differentiation and carcinoma formation are poorly understood. We previously reported that c-MYC overexpression stimulates SG differentiation. We now demonstrate roles for the androgen receptor (AR) and p53. MYC-induced SG differentiation was reduced in mice lacking a functional AR. High levels of MYC triggered a p53-dependent DNA damage response, leading to accumulation of proliferative SG p ...[more]

PMID: 23403291

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Project description:BackgroundProstate cancer is a major cause of cancer morbidity and mortality in men worldwide. Androgen deprivation therapy (ADT) has proven effective in early-stage androgen-sensitive disease, but prostate cancer gradually develops into an androgen-resistant metastatic state in the vast majority of patients. According to our oncogene-induced model for cancer development, senescence is a major tumor progression barrier. However, whether senescence is implicated in the progression of early-stage androgen-sensitive to highly aggressive castration-resistant prostate cancer (CRPC) remains poorly addressed.MethodsAndrogen-dependent (LNCaP) and -independent (C4-2B and PC-3) cells were treated or not with enzalutamide, an Androgen Receptor (AR) inhibitor. RNA sequencing and pathway analyses were carried out in LNCaP cells to identify potential senescence regulators upon treatment. Assessment of the invasive potential of cells and senescence status following enzalutamide treatment and/or RNAi-mediated silencing of selected targets was performed in all cell lines, complemented by bioinformatics analyses on a wide range of in vitro and in vivo datasets. Key observations were validated in LNCaP and C4-2B mouse xenografts. Senescence induction was assessed by state-of-the-art GL13 staining by immunocytochemistry and confocal microscopy.ResultsWe demonstrate that enzalutamide treatment induces senescence in androgen-sensitive cells via reduction of the replication licensing factor CDC6. Mechanistically, we show that CDC6 downregulation is mediated through endogenous activation of the GATA2 transcription factor functioning as a CDC6 repressor. Intriguingly, GATA2 levels decrease in enzalutamide-resistant cells, leading to CDC6 stabilization accompanied by activation of Epithelial-To-Mesenchymal Transition (EMT) markers and absence of senescence. We show that CDC6 loss is sufficient to reverse oncogenic features and induce senescence regardless of treatment responsiveness, thereby identifying CDC6 as a critical determinant of prostate cancer progression.ConclusionsWe identify a key GATA2-CDC6 signaling axis which is reciprocally regulated in enzalutamide-sensitive and -resistant prostate cancer environments. Upon acquired resistance, GATA2 repression leads to CDC6 stabilization, with detrimental effects in disease progression through exacerbation of EMT and abrogation of senescence. However, bypassing the GATA2-CDC6 axis by direct inhibition of CDC6 reverses oncogenic features and establishes senescence, thereby offering a therapeutic window even after acquiring resistance to therapy.

Project description:BACKGROUND:We conducted a randomized trial to evaluate the efficacy of heparinoid moisturization for radiation dermatitis. We report the time-course of sebum content after whole breast radiotherapy (WBRT) and the efficacy of heparinoid moisturizer. METHODS:Patients receiving adjuvant breast RT were randomly assigned into three groups; prophylaxis, post-WBRT and control groups. Patients used moisturizer on the irradiated breast from the beginning of RT in the prophylaxis group, 2?weeks post-RT in the post-WBRT group, and no moisturizer in the control group. Sebum content of the irradiated and non-irradiated breast was measured to assess sebaceous gland damage. Sebum composition was also analyzed. RESULTS:A total of 76 patients were analyzed; 30 in the post-WBRT group, 32 in the control group, 14 in the prophylaxis group. The sebum content in the irradiated breast significantly decreased after WBRT in the post-WBRT and control groups. The decrease was sustained in the control group. In the non-irradiated breast, sebum content also decreased after WBRT in the post-WBRT and control groups. After moisturizer application, sebum content by sebumeter returned to pre-RT level in the post-WBRT group, while the decrease was sustained in the control group. Sebum content measured by evaporative light scattering detector and sebumeter was similar in the control group, but the dissociation was observed after moisturizer application in the post-WBRT group. The proportion of wax esters decreased in the irradiated breast after WBRT. CONCLUSIONS:Radiotherapy significantly reduced sebum content in both irradiated and non-irradiated breast, indicating that RT caused quantifiably persistent sebaceous gland damage in irradiated sites and the surrounding tissue. Combined with the results from our previous study, heparinoid moisturizer treatment effectively prevents water loss by retaining oil contents on the skin surface. TRIAL REGISTRATION:UMIN, UMIN000005532 . Registered 1 April 2011.

Dataset Information

C-MYC-induced sebaceous gland differentiation is controlled by an androgen receptor/p53 axis.

Publications

c-MYC-induced sebaceous gland differentiation is controlled by an androgen receptor/p53 axis.

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