TY - JOUR
T1 - Tp73-As1 Is Induced By Yy1 During Tmz Treatment And Highly Expressed In The Aging Brain
AU - Mazor, Gal
AU - Smirnov, Dmitri
AU - David, Hila Ben
AU - Khrameeva, Ekaterina
AU - Toiber, Debra
AU - Rotblat, Barak
N1 - Publisher Copyright: © 2021 Mazor et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2021/6/15
Y1 - 2021/6/15
N2 - Aging is a factor associated with poor prognosis in glioblastoma (GBM). It is therefore important to understand the molecular features of aging contributing to GBM morbidity. TP73-AS1 is a long noncoding RNA (lncRNA) over expressed in GBM tumors shown to promote resistance to the chemotherapeutic temozolomide (TMZ), and tumor aggressiveness. How the expression of TP73-AS1 is regulated is not known, nor is it known if its expression is associated with aging. By analyzing transcriptional data obtained from natural and pathological aging brain, we found that the expression of TP73-AS1 is high in pathological and naturally aging brains. YY1 physically associates with the promoter of TP73-AS1 and we found that along with TP73-AS1, YY1 is induced by TMZ. We found that the TP73-AS1 promoter is activated by TMZ, and by YY1 over expression. Using CRISPRi to deplete YY1, we found that YY1 promotes up regulation of TP73-AS1 and the activation of its promoter during TMZ treatment. In addition, we identified two putative YY1 binding sites within the TP73-AS1 promoter, and used mutagenesis to find that they are essential for TMZ mediated promoter activation. Together, our data positions YY1 as an important TP73-AS1 regulator, demonstrating that TP73-AS1 is expressed in the natural and pathological aging brain, including during neurodegeneration and cancer. Our findings advance our understanding of TP73-AS1 expression, bringing forth a new link between TMZ resistance and aging, both of which contribute to GBM morbidity.
AB - Aging is a factor associated with poor prognosis in glioblastoma (GBM). It is therefore important to understand the molecular features of aging contributing to GBM morbidity. TP73-AS1 is a long noncoding RNA (lncRNA) over expressed in GBM tumors shown to promote resistance to the chemotherapeutic temozolomide (TMZ), and tumor aggressiveness. How the expression of TP73-AS1 is regulated is not known, nor is it known if its expression is associated with aging. By analyzing transcriptional data obtained from natural and pathological aging brain, we found that the expression of TP73-AS1 is high in pathological and naturally aging brains. YY1 physically associates with the promoter of TP73-AS1 and we found that along with TP73-AS1, YY1 is induced by TMZ. We found that the TP73-AS1 promoter is activated by TMZ, and by YY1 over expression. Using CRISPRi to deplete YY1, we found that YY1 promotes up regulation of TP73-AS1 and the activation of its promoter during TMZ treatment. In addition, we identified two putative YY1 binding sites within the TP73-AS1 promoter, and used mutagenesis to find that they are essential for TMZ mediated promoter activation. Together, our data positions YY1 as an important TP73-AS1 regulator, demonstrating that TP73-AS1 is expressed in the natural and pathological aging brain, including during neurodegeneration and cancer. Our findings advance our understanding of TP73-AS1 expression, bringing forth a new link between TMZ resistance and aging, both of which contribute to GBM morbidity.
KW - Long Noncoding Rna
KW - glioblastoma
UR - http://www.scopus.com/inward/record.url?scp=85108607777&partnerID=8YFLogxK
U2 - https://doi.org/10.18632/aging.203182
DO - https://doi.org/10.18632/aging.203182
M3 - Article
C2 - 34115613
SN - 1945-4589
VL - 13
SP - 14843
EP - 14861
JO - Aging
JF - Aging
IS - 11
ER -