Coactivator SRC-2–dependent metabolic reprogramming mediates prostate cancer survival and metastasis
Subhamoy Dasgupta, Nagireddy Putluri, Weiwen Long, Bin Zhang, Jianghua Wang, Akash K. Kaushik, James M. Arnold, Salil K. Bhowmik, Erin Stashi, Christine A. Brennan, Kimal Rajapakshe, Cristian Coarfa, Nicholas Mitsiades, Michael M. Ittmann, Arul M. Chinnaiyan, Arun Sreekumar, Bert W. O’Malley
Subhamoy Dasgupta, Nagireddy Putluri, Weiwen Long, Bin Zhang, Jianghua Wang, Akash K. Kaushik, James M. Arnold, Salil K. Bhowmik, Erin Stashi, Christine A. Brennan, Kimal Rajapakshe, Cristian Coarfa, Nicholas Mitsiades, Michael M. Ittmann, Arul M. Chinnaiyan, Arun Sreekumar, Bert W. O’Malley
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Research Article Oncology

Coactivator SRC-2–dependent metabolic reprogramming mediates prostate cancer survival and metastasis

Abstract

Metabolic pathway reprogramming is a hallmark of cancer cell growth and survival and supports the anabolic and energetic demands of these rapidly dividing cells. The underlying regulators of the tumor metabolic program are not completely understood; however, these factors have potential as cancer therapy targets. Here, we determined that upregulation of the oncogenic transcriptional coregulator steroid receptor coactivator 2 (SRC-2), also known as NCOA2, drives glutamine-dependent de novo lipogenesis, which supports tumor cell survival and eventual metastasis. SRC-2 was highly elevated in a variety of tumors, especially in prostate cancer, in which SRC-2 was amplified and overexpressed in 37% of the metastatic tumors evaluated. In prostate cancer cells, SRC-2 stimulated reductive carboxylation of α-ketoglutarate to generate citrate via retrograde TCA cycling, promoting lipogenesis and reprogramming of glutamine metabolism. Glutamine-mediated nutrient signaling activated SRC-2 via mTORC1-dependent phosphorylation, which then triggered downstream transcriptional responses by coactivating SREBP-1, which subsequently enhanced lipogenic enzyme expression. Metabolic profiling of human prostate tumors identified a massive increase in the SRC-2–driven metabolic signature in metastatic tumors compared with that seen in localized tumors, further implicating SRC-2 as a prominent metabolic coordinator of cancer metastasis. Moreover, SRC-2 inhibition in murine models severely attenuated the survival, growth, and metastasis of prostate cancer. Together, these results suggest that the SRC-2 pathway has potential as a therapeutic target for prostate cancer.

Authors

Subhamoy Dasgupta, Nagireddy Putluri, Weiwen Long, Bin Zhang, Jianghua Wang, Akash K. Kaushik, James M. Arnold, Salil K. Bhowmik, Erin Stashi, Christine A. Brennan, Kimal Rajapakshe, Cristian Coarfa, Nicholas Mitsiades, Michael M. Ittmann, Arul M. Chinnaiyan, Arun Sreekumar, Bert W. O’Malley

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Figure 3

SRC-2 coactivates SREBP1 to promote lipogenesis.

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SRC-2 coactivates SREBP1 to promote lipogenesis. (A) Luciferase reporter...
(A) Luciferase reporter assay in HeLa cells transiently transfected with a FASN-luciferase construct (–220 to +25 bp) in the presence of vector alone, SREBP-1, SRC-2, or a combination of both SRC-2 and SREBP-1 (n = 6). (B) Luciferase reporter assay in HeLa cells transiently transfected with an SCD-luciferase construct (–1,280 to +174 bp) in the presence of vector alone, SREBP-1, SRC-2, or a combination of both SRC-2 and SREBP-1 (n = 6). (C and D) Western blot analysis followed by luciferase reporter assay in PC-3 cells transfected with an FASN-luciferase construct in the presence of control siRNA (siNT), SRC-2-siRNA (siSRC-2), SREBP-1 siRNA (siSREBP-1), or a combination of both SRC-2 and SREBP-1. Semiquantitative levels of each band were analyzed by densitometry using UVP Vision Works LS software, and the relative values (compared with untreated) normalized to actin are indicated numerically under each lane. The full, uncut gels are shown in the Supplemental Material. (E) ChIP of SRC-2 and SREBP-1 from the stable C4-2 cells shNT and sh18 showing the recruitment of these 2 proteins on the FASN promoter. The amplicons tested were either from a proximal promoter region (–140 to –40 bp) or an unconserved upstream region (–2,000 bp) from the transcriptional start site. IgG antibody was used as a control, and data are presented as a percentage of input chromatin (n = 4). Schematic shows the SRE, GC box, E box, and TATA elements on the FASN promoter. Data represent the mean ± SEM. *P < 0.05 by 2-way ANOVA with Tukey’s multiple comparisons test (E) and **P < 0.001 by Student’s t test (A, B, and D).