RARγ: The Bone of Contention for Endothelial Cells in Prostate Cancer Metastasis.

Excessive bone deposition associated with prostate cancer bone metastases is believed to aid in metastatic progression. One mechanism of osteoblast expansion is the transdifferentiation of bone marrow endothelial cells. Prostate cancer cells contribute several secreted factors, including bone morphogenetic protein 4 (BMP4), to the microenvironment that support osteoblastic transdifferentiation. In this issue of Cancer Research, Yu and colleagues share their findings of how BMP-mediated endothelial conversion can be inhibited by treatment with retinoic acid receptor (RAR) agonists. Using agonists like the all-trans retinoic acid or palovarotene, the authors demonstrated the role of the interaction of BMP-activated SMAD1 with RARγ for osteoblastic differentiation. RARγ agonists potentiated the proteasomal degradation of the Smad1-RARγ complex, blocking BMP signaling. Because palovarotene is clinically effective in the treatment of aberrant bone formation found in fibrodysplasia ossificans progressiva, its repurposing for the treatment of osteoblastic cancer metastasis is promising. However, patient selection and dose-finding studies will be critical for the translation of these findings to complement standard of care for patients with bone metastatic prostate cancer. See related article by Yu et al., p. 3158.

Mitochondrial metabolism and calcium homeostasis in the development of NAFLD leading to hepatocellular carcinoma.

Non-alcoholic fatty liver disease (NAFLD) is a metabolic syndrome characterized by excessive accumulation of hepatic lipid droplets. The disease progresses with steatosis as the premise for hepatocytic damage and tissue scarring, often culminating in hepatocellular carcinoma (HCC). Perturbations in mitochondrial metabolism and energetics were found to be associated with, and often instrumental in various stages of this progression. Functional impairment of the mitochondria affects all aspects of cellular functioning and a particularly important one is calcium signalling. Changes in mitochondrial calcium specifically in hepatocytes of a fatty liver, is reflected by alterations in calcium signalling as well as calcium transporter activities. This deranged Ca2+ homeostasis aids in even more uptake of lipids into the mitochondria and a shift in equilibrium, both metabolically as well as in terms of energy production, leading to completely altered cellular states. These alterations have been reviewed as a perspective to understand the disease progression through NAFLD leading to HCC.

Beclin 1 controls pigmentation by changing the nuclear localization of melanogenic factor MITF.

The primary contributor for the determination of skin color is melanin, a pigment that is produced in specialized cells called melanocytes. At cellular level, melanin synthesis occurs through several enzymes like tyrosinase (TYR) and tyrosinase related proteins and the expression of these proteins are regulated transcriptionally by microphthalmia associated transcription factor (MITF). Melanin pigmentation is a complex process finely regulated by different transcription factors, structural proteins and enzymes. In recent times, several autophagic genes have been implicated in the regulation of pigmentation. Though previous report observed a visible loss of coat-color in heterozygous Beclin 1 mice, the role of this protein in pigmentation is yet to study in details. In this present work we intend to study the role of Beclin 1, a central autophagic factor, in pigmentation. Using human melanoma cells and primary melanocytes, we showed that Beclin 1 downregulation significantly decreased the melanin content, tyrosinase activity and the expression of TYR and tyrosinase related protein 1 (TYRP1). These effects were recapitulated in a Beclin 1 knockdown in vivo model of zebrafish. Most importantly, re-expression of Beclin 1 rescued the pigmentation-associated defects both in cellular and in organismal level indicating the specificity. Surprisingly, Beclin 1 knockdown cells did not show significant changes in MITF expression but the nuclear localization of MITF was altered. Together, these data suggest that indeed Beclin 1 is associated with melanogenesis and this effect is more likely exerted through the subcellular distribution rather than the change in expression of MITF.