Carnitine palmitoyltransferase I in human carcinomas: A novel role in histone deacetylation?

Abstract

KEy wordScarnitine palmitoyltransferase I (CPT1), fatty acid synthase (FAS), histone deacetylase activity, cancer, immunohistochemistry, metabolism, histone deacetylase inhibitors. ABBrEviAtionS ABStrACtCarnitine palmitoyl transferase I (CPT1) catalyzes the transport of long-chain fatty acids into mitochondria for b-oxidation. A link between CPT1 and apoptosis has been suggested on the basis of several experimental data. Nevertheless, results are contradictory about the effective role of CPT1 in cell survival control and cancer development. Conversely, Fatty acid synthase (FAS) enzyme, required for the synthesis of fatty acids, is found over-expressed in tumors and inhibition of FAS triggers apoptosis in human cancer cells.We have studied the tumor-specific modulation of CPT1 and FAS in human colorectal cancer (n = 11) and breast carcinomas (n = 24). CPT1 was significantly decreased in the cytoplasm of tumoral samples (p < 0.04), whereas FAS was increased (p < 0.04). A striking CPT1 nuclear localization was evident in the tumors (p < 0.04). In the nuclear environment the protein would modulate the levels of acetyl/acyl-CoA implicated in the regulation of gene transcription. At this purpose, we performed in vitro experiments using epithelial neoplastic (MCF-7, Caco-2, HepG2 cells) and non neoplastic cell lines (MCF-12F) confirming a nuclear localization of CPT1 protein exclusively in neoplastic cells. Moreover histone deacetylase (HDAC) activity showed significantly higher levels in nuclear extracts from neoplastic than from control cells. HDAC1 and CPT1 proteins coimmunoprecipitated in nuclear extracts from MCF-7 cells. The treatment with HDAC inhibitors such as trichostatin A and butyrate significantly decreased nuclear expression of CPT1 and its bond to HDAC1. We also identified the existence of CPT1A mRNA transcript variant 2 in MCF-7, beside to the classic isoform 1.The peculiar localization of CPT1 in the nuclei of human carcinomas and the disclosed functional link between nuclear CPT1 and HDAC1 propose a new role of CPT1 in the histonic acetylation level of tumors.

Chapter 3 The Shifting Balance Between CLU Forms During Tumor Progression

“…Mazzarelli et al (2007) recently observed that the CPT I was significantly decreased in the mitochondria, and it strikingly localized in the nuclei of tumoral tissues (colon, breast, liver, ovary). At this purpose, in vitro experiments using epithelial neoplastic (MCF-7, Caco-2, HepG2) cells and nonneoplastic cell lines (MCF-12F) confirmed a nuclear localization of CPT1 protein exclusively in neoplastic cells.…”

Carnitine palmitoyltransferase 1C: From cognition to cancer

“…The liver isoform, CPT1A, is overexpressed mainly in cancers affecting blood cells, such as chronic myeloid leukemia and acute myeloid leukemia [121]. It has been proposed that CPT1A contributes to cell survival, not only by increasing FAO [122] but also stimulating histone acetylase activity in the nucleus [123]. Interestingly, Cpt1c has also emerged as a key gene in tumor cell survival in certain types of cancer [124].…”

Molecular Pathways: Tumor Cells Co-opt the Brain-Specific Metabolism GeneCPT1Cto Promote Survival

“…CML, chronic myelogenous leukemia; AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia. for fulfilling their metabolic needs, particularly when more broadly expressed family members, namely CPT1A and CPT1B, are also available but apparently not activated in cancer cells (44). Presumably, both CPT1A and CPT1B can also increase FAO (45,46), so it stands to reason that CPT1C upregulation must provide a special activity that spurs tumor growth.…”