Highlights of This Issue

Abstract

Satellite RNA transcribed from tandem repeat arrays near centromeric regions in chromosomes are aberrantly and highly expressed in the early stages of pancreatic carcinogenesis. Kishikawa and colleagues generated a mouse major satellite (MajSAT) RNA-expressing mouse model and demonstrated that MajSAT RNA increases DNA damage by inhibiting stress-responded nuclear translocation of YBX1 and accelerates tumor formation in the pancreas of Kras-mutant mice, which is consistent with previous in vitro findings. This study indicates that MajSAT RNA play a role as an intrinsic mutagen in the process of pancreatic cancer development.Unrestricted replicative growth conferred by stable telomere maintenance is one of the hallmarks of cancer, and most of human cancers achieve this through the aberrant expression of telomerase. Therapeutic use of telomerase targeting agents was limited by a substantial lag phase preceding telomere shortening and the onset of cytotoxicity. This study, by Thompson and colleagues, demonstrates that telomerase facilitates the kinetics of telomere cap formation and passage through G2 phase. Transient telomerase inhibition results in a prolonged ATM-dependent DNA-damage signal that alters the cell cycle profile. This data provides the biological rationale for exploring clinical telomerase inhibition strategies that leverage telomere-length-independent mechanisms of activity.Cancer-associated adipocytes play a vital role in ovarian cancer (OC) progression. Previous studies demonstrate effective treatment of platinum-resistant OC with epigenetic therapy. However, effect of epigenetic therapy on the tumor microenvironment (TME) is not well understood. Tang and colleagues examined the effects of a DNMT inhibitor, guadecitabine, on adipocytes in the context of the tumor microenvironment. Guadecitabine treatment of adipocytes decreased OC cell migration and invasion partly through upregulation of SUSD2, a secreted tumor suppressor. These findings suggest that in addition to direct effects on cancer cells, epigenetic therapy impcats the tumor microenvironment through altered cytokine secretion to prevent OC metastasis.The nuclear receptor CAR, activated by phenobarbital, preferentially promotes hepatocellular carcinoma (HCC) development in male mice. Now growth arrest and DNA-damage-inducible 45 beta (GADD45B) is characterized as a key target of CAR in hepatocyte proliferation. CAR directly interacts and prevents GADD45B from forming a complex with MKK6 to repress the activity of the p38 MAPK tumor suppressor. Experiments with GADD45B knockout mice demonstrate that GADD45B mediates a phenobarbital-induced and male-specific hepatocyte proliferative phenotype. Thus, this study provides new mechanistic insight into phenobarbital-promoted HCC development.