Prostate Tumor Growth Is Impaired by CtBP1 Depletion in High-Fat Diet–Fed Mice

Abstract

Purpose: Clinical and epidemiologic data suggest that obesity is associated with more aggressive forms of prostate cancer, poor prognosis, and increased mortality. C-terminal-binding protein 1 (CtBP1) is a transcription repressor of tumor suppressor genes and is activated by NADH binding. High calorie intake decreases intracellular NAD þ /NADH ratio. The aim of this work was to assess the effect of high-fat diet (HFD) and CtBP1 expression modulation over prostate xenograft growth. Experimental Design: We developed a metabolic syndrome-like disease in vivo model by feeding male nude mice with HFD during 16 weeks. Control diet (CD)-fed animals were maintained at the same conditions. Mice were inoculated with PC3 cells stable transfected with shCtBP1 or control plasmids. Genome-wide expression profiles and Gene Set Enrichment Analysis (GSEA) were performed from PC3. shCtBP1 versus PC3.pGIPZ HFD-fed mice tumors.Results: No significant differences were observed in tumor growth on CD-fed mice; however, we found that only 60% of HFD-fed mice inoculated with CtBP1-depleted cells developed a tumor. Moreover these tumors were significantly smaller than those generated by PC3.pGIPZ control xenografts. We found 823 genes differentially expressed in shCtBP1 tumors from HFD-fed mice. GSEA from expression dataset showed that most of these genes correspond to cell adhesion, metabolic process, and cell cycle.Conclusions: Metabolic syndrome-like diseases and CtBP1 expression cooperate to induce prostate tumor growth. Hence, targeting of CtBP1 expression might be considered for prostate cancer management and therapy in the subset of patients with metabolic syndromes. Clin Cancer Res; 20(15); 4086-95. Ó2014 AACR.

CLCA2 epigenetic regulation by CTBP1, HDACs, ZEB1, EP300 and miR‐196b‐5p impacts prostate cancer cell adhesion and EMT in metabolic syndrome disease

“…PC3 (ATCC: CRL‐1435), 22Rv1 (ATCC: CRL‐2505), LNCaP (ATCC: CRL‐1740), C4‐2 cell lines and its stable derivatives were grown in RPMI 1640 (Invitrogen) supplemented with 10% of fetal bovine serum (FBS) and antibiotics in a 5% CO 2 humidified atmosphere at 37°C. PC3.shCTBP1 and its control (PC3.pGIPZ) stable cell lines were described previously . PC3.shCLCA2 (shCLCA2) and its control PC3.pGIPZ (pGIPZ) cells lines were generated by lentiviral infection as described previously using pGIPZ.shCLCA2 or pGIPZ plasmids.…”

“…CTBP1 is a transcriptional co‐repressor of tumor suppressor genes that is activated with much higher affinity by NADH (>100‐fold) compared to NAD + . Therefore, we generated a MeS mice model by chronically feeding animals with a high fat diet (HFD) and found that CTBP1 depletion in MeS mice dramatically decreased PCa growth …”

The Role of CtBP1 in Oncogenic Processes and Its Potential as a Therapeutic Target

“…Following these early studies, CtBP1 overexpression has been observed in a number of different cancers, including prostate (64, 68), melanomas (69), colon (70), leukemia (71–73), ovarian (74, 75), and breast cancer (76, 77), among others. In most cases CtBP1 overexpression is pro-tumorigenic.…”

“…Consistent with these findings, elevated NADH levels under hypoxic conditions associated with solid tumors repress the transcription of the CtBP target gene, E-cadherin, and increases cell migration, both of which are reversed by CtBP knockdown (23). Furthermore, increased NADH levels resulting from high-caloric intake, promotes both prostate and breast carcinogenesis in a CtBP1-dependent manner in vivo (45, 64, 65). Since CtBP1 is the more commonly studied CtBP family member in cancer, the remainder of this review will focus on CtBP1, its known oncogenic roles, and the possibility of therapeutically targeting this protein.…”

Hierarchical Feature Selection Incorporating Known and Novel Biological Information: Identifying Genomic Features Related to Prostate Cancer Recurrence

“…For the genes within this pathway, C-terminal binding protein 1 (CtBP1) is a transcriptional corepressor of the androgen receptor that is known to play a role in multiple cancers. In prostate cancer, CtBP1 affects proliferation, invasion, metabolism, growth, and metastasis(Moiola et al, 2014; Wang et al, 2012). Vascular endothelial growth factor A (VEGFA) is the critical signaling ligand for angiogenesis, or growth of new blood vessels, that is highly expressed in prostate cancer(Woollard et al, 2013).…”