Biology subjects

Tsujino, T.

Publications and source records attributed to Tsujino, T..

3 recordsLinked to original sources

bioRxiv2022

CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer

Prostate cancer (PCa) harboring BRCA1/2 mutations is often exquisitely sensitive to PARP inhibition. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical response to PARP inhibitors (PARPis). Here, we perform genome-wide CRISPR-Cas9 knockout screens in BRCA1/2-proficient PCa cell lines and identify novel genes whose loss has a profound impact on PARPi sensitivity and resistance. Specifically, MMS22L deletion, frequently observed (up to 14%) in PCa, renders cells hypersensitive to PARPis by disrupting RAD51 loading required for homologous recombination repair, although this response is TP53-dependent. Unexpectedly, loss of CHEK2 confers resistance rather than sensitivity to PARPis in PCa cells through increased expression of BRCA2, a target of CHEK2-TP53-E2F7-mediated transcriptional repression. Combined PARP and ATR inhibition overcomes PARPi resistance caused by CHEK2 loss. Our findings may inform the use of PARPis beyond BRCA1/2-deficient tumors and support reevaluation of currently used biomarkers for PARPi treatment in PCa.

cancer biology↗

bioRxiv2022

Iron Deficiency Induces Heart Failure with Ectopic Cardiac Calcification in Mice with Metabolic Syndrome

Iron deficiency is linked to worse clinical status and outcomes in heart failure. Although metabolic syndrome contributes to the development of heart failure, the impact of iron deficiency in heart failure complicated with metabolic syndrome remains obscure. KKAy mice were used as a model of metabolic syndrome. Four-week-old male C57BL/6J and KKAy mice were fed either a normal diet or iron-restricted (IR) diet for 12 weeks. During the experiment, 40% of mice died due to pulmonary congestion in KKAy mice with IR diet (KKAy-IR), while no mice died in other groups. Necropsy showed the presence of multiple white lesions on the cardiac surface in those KKAy-IR mice. Echocardiography and histological analyses revealed that KKAy-IR mice exhibited cardiac hypertrophy and cardiac dysfunction with cardiac calcification. Cardiac mRNA of ectonucleotide pyrophosphatase/phosphodiesterase-1 (Enpp1), a key enzyme for bone mineralization, was highly abundant in KKAy-IR mice. Of note, iron restriction-induced cardiac calcification and dysfunction were attenuated by etidronate, an inhibitor of bone mineralization, with decreased cardiac Enpp1 mRNA abundance in KKAy-IR mice. In conclusion, iron deficiency leads to ectopic cardiac calcification and dysfunction with the increase of Enpp1 in metabolic syndrome model mice.

pathology↗

bioRxiv2021

RB1 loss overrides PARP inhibitor sensitivity driven by RNASEH2B loss in prostate cancer

Current targeted cancer therapies are largely guided by mutations of a single gene, which overlooks concurrent genomic alterations. Here, we show that RNASEH2B, RB1, and BRCA2, three closely located genes on chromosome 13q, are frequently deleted in prostate cancer individually or jointly. Loss of RNASEH2B confers cancer cells sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition due to impaired ribonucleotide excision repair and PARP trapping. When co-deleted with RB1, however, cells lose their sensitivity, in part, through E2F1-induced BRCA2 expression, thereby enhancing homologous recombination repair capacity. Nevertheless, loss of BRCA2 re-sensitizes RNASEH2B/RB1 co-deleted cells to PARP inhibition. Our results may explain some of the disparate clinical results from PARP inhibition due to interaction between multiple genomic alterations and support a comprehensive genomic testing to determine who may benefit from PARP inhibition. Finally, we show that ATR inhibition can disrupt E2F1-induced BRCA2 expression and overcome PARP inhibitor resistance caused by RB1 loss.

cancer biology↗