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Recently, Alexandra M.
Amen of the Department of Neurosurgery, University of California, San Francisco, et al.
reported the effect of GABPB1L on the growth of TERTpMut GBM and the effect of temozolomide chemotherapy; The article was published online in the March 2021 issue of PNAS
.
——Excerpt from the article chapter
【Ref: Amen AM, et al.
Proc Natl Acad Sci U S A.
2021 Mar 30; 118(13):e2008772118.
doi: 10.
1073/pnas.
2008772118.
】
Research background
Glioblastoma (GBM) is a common intracranial malignancy in adults; Transcriptional activation of telomerase reverse transcriptase (TERT) is a critical step
in tumorigenesis.
However, the TERT promoter mutant (TERTpMut) type GBM exhibits a dependence on
the GA-binding protein (GABP) isomer, GABPB1L.
Recently, Alexandra M.
Amen of the Department of Neurosurgery, University of California, San Francisco, USA, reported the effect of GABPB1L on the growth of TERTpMut GBM and the effect of temozolomide (TMZ) chemotherapy.
The article was published online in the March 2021 issue of PNAS
.
Research Methods
The authors evaluated the effect of GABPB1L on the growth of TERTpMut GBM and the effect of
temozolomide chemotherapy through protein purification, plasmid and lentiviral construction, CRISPR-Cas9 and other techniques.
Results of the study
The results show that the regulation of TERTpMut on TERT expression depends on GABPB1L: The authors first constructed doxycycline-mediated shGB1S and shGB1L, and found that
they induced a decrease
in GABPB1S and GABPB1L expression in both TERTpMut type U251 and TERTpWT type LN18.
Subsequently, the authors analyzed TERT mRNA and telomerase activity and found that the regulation of TERT expression by TERTpMut is dependent on GABPB1L
.
Further study of its interaction mechanism found that TERTpMut increases the affinity for the heterotetramer complex of GABPB1L, thereby driving TERT reactivation (Figure 1
).
Figure 1.
TERTpMut's regulation of TERT expression relies on GABPB1L
.
GABPB1L loss inhibits TERTpMut GBM cell growth:
The authors used CRISPR-Cas9 and sgRNA techniques to cause the expression loss of GABPB1L in three TERTpMut GBM cell lines (U-251, LN-229 and T98G) and four TERTpWT GBM cell lines, and found that GABPB1L loss significantly inhibited the growth and survival of TERTpMut GBM cells, while slowing down tumor growth in tumor-bearing mice and improving the median survival of tumor-bearing mice (Figure
。
GABPB1L loss inhibits TERTpMut GBM cell growth
.
GABPB1L loss can increase the TMZ chemotherapy effect of TERTpMut GBM:
In TERTpMut GBM cells, GABPB1L loss leads to decreased TERT expression, slowing down DNA damage repair, inducing cell cycle arrest, and ultimately reducing GBM cell viability
.
In the CDX model of TERTpMut GBM cell U251, GABPB1L loss and TERT can effectively slow tumor growth, prolong survival, and reduce the proportion
of Ki-67-positive tumor cells.
What's more, GABPB1L loss and TERT were able to increase TMZ chemotherapy effects in TERTpMut GBM cells (Figure 3
).
Figure 3.
GABPB1L loss increases TMZ chemotherapy effect
of TERTpMut type GBM.
Conclusion of the study
In summary, GABPB1L loss combined with TMZ therapy increased the efficacy of TERTpMut GBM therapy and improved prognosis
in patients with TERTpMut GBM.
