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Targeting the MLL complex in castration-resistant prostate cancer.

Malik R, Khan AP, Asangani IA, Cieślik M, Prensner JR, Wang X, Iyer MK, Jiang X, Borkin D, Escara-Wilke J, Stender R, Wu YM, Niknafs YS, Jing X, Qiao Y, Palanisamy N, Kunju LP, Krishnamurthy PM, Yocum AK, Mellacheruvu D, Nesvizhskii AI, Cao X, Dhanasekaran SM, Feng FY, Grembecka J, Cierpicki T, Chinnaiyan AM - Nat. Med. (2015)

Bottom Line: Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling.AR directly interacts with the MLL complex via the menin-MLL subunit.Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice.

View Article: PubMed Central - PubMed

Affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.

ABSTRACT
Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has focused on targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via the menin-MLL subunit. Menin expression is higher in CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer.

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Menin is upregulated in both localized and metastatic castration resistant prostate cancer. (a,b) Menin expression in RNA-Sequencing (RNA-Seq) data from benign (n=38), localized (PCa) (n=118) and metastatic tumor (Met) (n=55) prostate tissues in Michigan Center for Translational Pathology (MCTP) cohort (a) and in benign (n=37) and localized tumor (n=137) prostate tissue samples in The Cancer Genome Atlas (TCGA) (b). The y-axis denotes Fragments Per Kilobase of transcript per Million mapped reads (FPKM). P values are calculated using one-way ANOVA (a) or t-test (b) (c,d) Menin transcript expression in multiple prostate cancer microarray studies from the Oncomine database. Datasets were analyzed for menin expression in benign vs localized prostate cancer (PCa) (c) and PCa vs metastatic castrate resistant prostate cancer (Met) (d). Study first author, statistical significance and number of samples are indicated. P values are calculated using two-sample, one-tailed Welch’s t-test. (e) Expression of menin protein in benign (n=6), PCa (n=5) and CRPC (n=8) tissues was assessed by immunoblotting. Loading control, β-actin (f) Menin mRNA expression correlates with poor overall survival by Kaplan-Meier analyses of prostate cancer outcome in the Nakagawa study. Samples were divided into quartiles based on menin expression. Expression of menin in the middle two quartiles was merged (25–75%). ** P<0.001, compared to low menin expressers based on log-rank (Mantel-Cox) test.
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Figure 5: Menin is upregulated in both localized and metastatic castration resistant prostate cancer. (a,b) Menin expression in RNA-Sequencing (RNA-Seq) data from benign (n=38), localized (PCa) (n=118) and metastatic tumor (Met) (n=55) prostate tissues in Michigan Center for Translational Pathology (MCTP) cohort (a) and in benign (n=37) and localized tumor (n=137) prostate tissue samples in The Cancer Genome Atlas (TCGA) (b). The y-axis denotes Fragments Per Kilobase of transcript per Million mapped reads (FPKM). P values are calculated using one-way ANOVA (a) or t-test (b) (c,d) Menin transcript expression in multiple prostate cancer microarray studies from the Oncomine database. Datasets were analyzed for menin expression in benign vs localized prostate cancer (PCa) (c) and PCa vs metastatic castrate resistant prostate cancer (Met) (d). Study first author, statistical significance and number of samples are indicated. P values are calculated using two-sample, one-tailed Welch’s t-test. (e) Expression of menin protein in benign (n=6), PCa (n=5) and CRPC (n=8) tissues was assessed by immunoblotting. Loading control, β-actin (f) Menin mRNA expression correlates with poor overall survival by Kaplan-Meier analyses of prostate cancer outcome in the Nakagawa study. Samples were divided into quartiles based on menin expression. Expression of menin in the middle two quartiles was merged (25–75%). ** P<0.001, compared to low menin expressers based on log-rank (Mantel-Cox) test.

Mentions: Given the importance of the MLL complex in solid tumors23–25, we examined menin expression in a set of human prostate cancer tissue samples. Using RNA-Seq we observed that menin expression was associated with disease progression with significantly elevated levels in metastatic prostate cancer compared to hormone naïve prostate cancer and benign prostate (Fig. 5a). We validated this observation using prostate cancer samples from The Cancer Genome Atlas (TCGA); that also demonstrated menin up-regulation in prostate cancer compared to benign controls (Fig. 5b). Notably, among other members of the MLL complex, while WDR5 transcript levels was elevated in metastatic prostate cancer MLL, MLL4, ASH2L and RBBP5 were not differential (Supplementary Fig. 8a–e). We next analyzed expression of menin in published microarray datasets using the Oncomine database29. Similar to the RNA-Seq data, menin expression was elevated in localized and metastatic prostate cancer in multiple published studies (Fig. 5c–d). Similarly, Menin protein was also elevated in during prostate cancer progression, with notably higher protein levels in metastatic compared to localized disease (Fig. 5e).


Targeting the MLL complex in castration-resistant prostate cancer.

Malik R, Khan AP, Asangani IA, Cieślik M, Prensner JR, Wang X, Iyer MK, Jiang X, Borkin D, Escara-Wilke J, Stender R, Wu YM, Niknafs YS, Jing X, Qiao Y, Palanisamy N, Kunju LP, Krishnamurthy PM, Yocum AK, Mellacheruvu D, Nesvizhskii AI, Cao X, Dhanasekaran SM, Feng FY, Grembecka J, Cierpicki T, Chinnaiyan AM - Nat. Med. (2015)

Menin is upregulated in both localized and metastatic castration resistant prostate cancer. (a,b) Menin expression in RNA-Sequencing (RNA-Seq) data from benign (n=38), localized (PCa) (n=118) and metastatic tumor (Met) (n=55) prostate tissues in Michigan Center for Translational Pathology (MCTP) cohort (a) and in benign (n=37) and localized tumor (n=137) prostate tissue samples in The Cancer Genome Atlas (TCGA) (b). The y-axis denotes Fragments Per Kilobase of transcript per Million mapped reads (FPKM). P values are calculated using one-way ANOVA (a) or t-test (b) (c,d) Menin transcript expression in multiple prostate cancer microarray studies from the Oncomine database. Datasets were analyzed for menin expression in benign vs localized prostate cancer (PCa) (c) and PCa vs metastatic castrate resistant prostate cancer (Met) (d). Study first author, statistical significance and number of samples are indicated. P values are calculated using two-sample, one-tailed Welch’s t-test. (e) Expression of menin protein in benign (n=6), PCa (n=5) and CRPC (n=8) tissues was assessed by immunoblotting. Loading control, β-actin (f) Menin mRNA expression correlates with poor overall survival by Kaplan-Meier analyses of prostate cancer outcome in the Nakagawa study. Samples were divided into quartiles based on menin expression. Expression of menin in the middle two quartiles was merged (25–75%). ** P<0.001, compared to low menin expressers based on log-rank (Mantel-Cox) test.
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Related In: Results  -  Collection

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Figure 5: Menin is upregulated in both localized and metastatic castration resistant prostate cancer. (a,b) Menin expression in RNA-Sequencing (RNA-Seq) data from benign (n=38), localized (PCa) (n=118) and metastatic tumor (Met) (n=55) prostate tissues in Michigan Center for Translational Pathology (MCTP) cohort (a) and in benign (n=37) and localized tumor (n=137) prostate tissue samples in The Cancer Genome Atlas (TCGA) (b). The y-axis denotes Fragments Per Kilobase of transcript per Million mapped reads (FPKM). P values are calculated using one-way ANOVA (a) or t-test (b) (c,d) Menin transcript expression in multiple prostate cancer microarray studies from the Oncomine database. Datasets were analyzed for menin expression in benign vs localized prostate cancer (PCa) (c) and PCa vs metastatic castrate resistant prostate cancer (Met) (d). Study first author, statistical significance and number of samples are indicated. P values are calculated using two-sample, one-tailed Welch’s t-test. (e) Expression of menin protein in benign (n=6), PCa (n=5) and CRPC (n=8) tissues was assessed by immunoblotting. Loading control, β-actin (f) Menin mRNA expression correlates with poor overall survival by Kaplan-Meier analyses of prostate cancer outcome in the Nakagawa study. Samples were divided into quartiles based on menin expression. Expression of menin in the middle two quartiles was merged (25–75%). ** P<0.001, compared to low menin expressers based on log-rank (Mantel-Cox) test.
Mentions: Given the importance of the MLL complex in solid tumors23–25, we examined menin expression in a set of human prostate cancer tissue samples. Using RNA-Seq we observed that menin expression was associated with disease progression with significantly elevated levels in metastatic prostate cancer compared to hormone naïve prostate cancer and benign prostate (Fig. 5a). We validated this observation using prostate cancer samples from The Cancer Genome Atlas (TCGA); that also demonstrated menin up-regulation in prostate cancer compared to benign controls (Fig. 5b). Notably, among other members of the MLL complex, while WDR5 transcript levels was elevated in metastatic prostate cancer MLL, MLL4, ASH2L and RBBP5 were not differential (Supplementary Fig. 8a–e). We next analyzed expression of menin in published microarray datasets using the Oncomine database29. Similar to the RNA-Seq data, menin expression was elevated in localized and metastatic prostate cancer in multiple published studies (Fig. 5c–d). Similarly, Menin protein was also elevated in during prostate cancer progression, with notably higher protein levels in metastatic compared to localized disease (Fig. 5e).

Bottom Line: Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling.AR directly interacts with the MLL complex via the menin-MLL subunit.Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice.

View Article: PubMed Central - PubMed

Affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.

ABSTRACT
Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has focused on targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via the menin-MLL subunit. Menin expression is higher in CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer.

Show MeSH
Related in: MedlinePlus