Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator PGC1α suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is down-regulated in prostate cancer and associated to disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an Oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α-ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment.

No abstract

Townes-Brocks syndrome (TBS) is characterized by a spectrum of malformations in the digits, ears, and kidneys. These anomalies overlap those seen in a growing number of ciliopathies, which are genetic syndromes linked to defects in the formation or function of the primary cilia. TBS is caused by mutations in the gene encoding the transcriptional repressor SALL1 and is associated with the presence of a truncated protein that localizes to the cytoplasm. Here, we provide evidence that SALL1 mutations might cause TBS by means beyond its transcriptional capacity. By using proximity proteomics, we show that truncated SALL1 interacts with factors related to cilia function, including the negative regulators of ciliogenesis CCP110 and CEP97. This most likely contributes to more frequent cilia formation in TBS-derived fibroblasts, as well as in a CRISPR/Cas9-generated model cell line and in TBS-modeled mouse embryonic fibroblasts, than in wild-type controls. Furthermore, TBS-like cells show changes in cilia length and disassembly rates in combination with aberrant SHH signaling transduction. These findings support the hypothesis that aberrations in primary cilia and SHH signaling are contributing factors in TBS phenotypes, representing a paradigm shift in understanding TBS etiology. These results open possibilities for the treatment of TBS.

Primary cilia are sensory organelles crucial for cell signaling during development and organ homeostasis. Cilia arise from centrosomes and their formation and function is governed by numerous factors. Through our studies on Townes-Brocks Syndrome (TBS), a rare disease linked to abnormal cilia formation in human fibroblasts, we uncovered the leucine-zipper protein LUZP1 as an interactor of truncated SALL1, a dominantly-acting protein causing the disease. Using TurboID proximity labeling and pulldowns, we show that LUZP1 associates with factors linked to centrosome and actin filaments. Here, we show that LUZP1 is a cilia regulator. It localizes around the centrioles and to actin cytoskeleton. Loss of LUZP1 reduces F-actin levels, facilitates ciliogenesis and alters Sonic Hedgehog signaling, pointing to a key role in cytoskeleton-cilia interdependency. Truncated SALL1 increases the ubiquitin proteasome-mediated degradation of LUZP1. Together with other factors, alterations in LUZP1 may be contributing to TBS etiology.

Oncogene addiction postulates that the survival and growth of certain tumor cells is dependent upon the activity of one oncogene, despite their multiple genetic and epigenetic abnormalities. This phenomenon provides a foundation for molecular targeted therapy and a rationale for oncogene-based stratification. We have previously reported that the Promyelocytic Leukemia protein (PML) is upregulated in triple negative breast cancer (TNBC) and it regulates cancer-initiating cell function, thus suggesting that this protein can be therapeutically targeted in combination with PML-based stratification. However, the effects of PML perturbation on the bulk of tumor cells remained poorly understood. Here we demonstrate that TNBC cells are addicted to the expression of this nuclear protein. PML inhibition led to a remarkable growth arrest combined with features of senescence in vitro and in vivo. Mechanistically, the growth arrest and senescence were associated to a decrease in MYC and PIM1 kinase levels, with the subsequent accumulation of CDKN1B (p27), a trigger of senescence. In line with this notion, we found that PML is associated to the promoter regions of MYC and PIM1, consistent with their direct correlation in breast cancer specimens. Altogether, our results provide a feasible explanation for the functional similarities of MYC, PIM1, and PML in TNBC and encourage further study of PML targeting strategies for the treatment of this breast cancer subtype.

LUZP1 is a centrosomal and actin cytoskeleton-localizing protein that regulates both ciliogenesis and actin filament bundling. As the cytoskeleton and cilia are implicated in metastasis and tumor suppression, we examined roles for LUZP1 in the context of cancer. Here we show that LUZP1 exhibits frequent genomic aberrations in cancer, with a predominance of gene deletions. Furthermore, we demonstrate that CRISPR/Cas9-mediated loss of Luzp1 in mouse fibroblasts promotes cell migration and invasion features, reduces cell viability, and increases cell apoptosis, centriole numbers, and nuclear size while altering the actin cytoskeleton. Loss of Luzp1 also induced changes to ACTR3 (Actin Related Protein 3, also known as ARP3) and phospho-cofilin ratios, suggesting regulatory roles in actin polymerization, beyond its role in filament bundling. Our results point to an unprecedented role for LUZP1 in the regulation of cancer features through the control of actin cytoskeleton.

36Primary cilia are sensory organelles that are crucial for cell signaling during 37 development and organ homeostasis. Cilia arise from the centrosome and their 38 formation is governed by numerous regulatory factors. We show that the leucine-zipper 39 protein LUZP1 localizes to the pericentriolar material and actin cytoskeleton. Using 40TurboID proximity labeling and pulldowns, LUZP1 associates with factors linked to 41 centrosome and actin filaments. Loss of LUZP1 reduces F-actin levels, facilitating 42 ciliogenesis and altering Sonic Hedgehog signaling, pointing to a key role in the 43 cytoskeleton-cilia interdependency. Moreover, we show that LUZP1 interacts with a 44 truncated form of the transcription factor SALL1 that causes Townes-Brocks Syndrome. 45 TBS is characterized by digit, heart and kidney malformations and is linked in part to 46 defective cilia. Truncated SALL1 increases the ubiquitin proteasome-mediated 47 51Primary cilia are sensory organelles that have a crucial role in cell signaling, 52 polarity and protein trafficking during development and organ homeostasis. 53 Importantly, the involvement of primary cilia in the above-mentioned processes is 54 frequently due to its role in Sonic Hedgehog (Shh) pathway regulation (1). Briefly, Shh 55 activation through its receptor PTCH1 leads to ciliary enrichment of the transmembrane 56 protein Smoothened (SMO), with concomitant conversion of the transcription factor 57 GLI3 from a cleaved repressor form to a full-length activator form, leading to activation 58 of Shh target genes. Two such genes are PTCH1 and GLI1 (encoding the Shh receptor 59 and a transcriptional activator, respectively), exemplifying the feedback and fine-tuning 60 of the Shh pathway. 61Cilia arise from the centrosome, a cellular organelle composed of two barrel-62 shaped microtubule-based structures called the centrioles. Primary cilia formation is 63 very dynamic throughout the cell cycle. Cilia are nucleated from the mother centriole 64 (MC) at the membrane-anchored basal body upon entry into the G0 phase, and they 65 reabsorb as cells progress from G1 to S phase, completely disassembling in mitosis (2). 66Centrioles are surrounded by protein-based matrix pericentriolar material (PCM) (3, 4). 67In eukaryotic cells, PCM proteins are concentrically arranged around a centriole in a 68 highly organized manner (5-8). Based on this observation, proper positioning and 69 organization of PCM proteins may be important for promoting different cellular 70 processes in a spatially regulated way (9). Not surprisingly, aberrations in the function 71 of PCM scaffolds are also associated with many human diseases, including cancer and 72 ciliopathies (10, 11). 73Cilia assembly and disassembly are regulated by diverse factors, including the 74 main cilia suppressor proteins CCP110 and CEP97 and the actin cytoskeleton. CCP110 75 4 and CEP97 form a complex that, when removed from the MC, allows ciliogenesis (12). 76The regulation of actin dynamics is also considered a major ciliogenesis driver in 7...

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