TY - JOUR
T1 - Protein arginine methyltransferase 5 as a therapeutic target for kras mutated colorectal cancer
AU - Shifteh, David
AU - Sapir, Tzuriel
AU - Pahmer, Moshe
AU - Haimowitz, Adam
AU - Goel, Sanjay
AU - Maitra, Radhashree
N1 - Funding Information:
Funding: This research was funded by a start-up fund #2A4108, as well as an Alexander Fund 252869-252929 provided by the Yeshiva University Office of the Provost to Radhashree Maitra.
Funding Information:
Acknowledgments: We would like to thank Selma Botman, the Yeshiva University Provost and Vice President for Academic Affairs, for graciously providing the start-up funding to Radhashree Maitra for this research. We would also like to thank Caro-Lyne DesRoches, our lab’s Biosciences Account Manager, for all of her time and support in helping us to obtain all of the necessary equipment for this research. Lastly, we would like to thank the Yeshiva College biology department for providing us with the required instruments to complete this work.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/8
Y1 - 2020/8
N2 - Nearly 45% of colorectal cancer (CRC) patients harbor a mutation in their KRAS gene for which, despite many years of research, there are still no targeted therapies available. Protein Arginine Methyltransferase 5 (PRMT5) is a transcription regulator for multiple cellular processes that is currently being tested as a potential target in several cancer types. PRMT5 has been previously shown to be overexpressed in approximately 75% of CRC patient tumor samples, as well as negatively correlated with CRC patient survival. Here, we provide evidence that PRMT5 can act as a surrogate target for mutated KRAS in CRC. Our findings show that PRMT5 expression is upregulated, as well as positively correlated with KRAS expression, in CRC patient datasets. Moreover, our results reveal that PRMT5 is further overexpressed in KRAS mutant CRC cells when compared to KRAS wild type (WT) CRC cells at both the transcriptional and translational levels. Additionally, our data demonstrate that this further overexpression of PRMT5 in the KRAS mutant CRC cells affects an even greater degree of growth inhibition, apoptosis, and cell cycle arrest, following treatment with PRMT5 inhibitor, when compared to the KRAS WT CRC cells. Our research therefore suggests for the first time that PRMT5 and KRAS may crosstalk, and thus, PRMT5 can potentially be used as a surrogate target for mutated KRAS in CRC.
AB - Nearly 45% of colorectal cancer (CRC) patients harbor a mutation in their KRAS gene for which, despite many years of research, there are still no targeted therapies available. Protein Arginine Methyltransferase 5 (PRMT5) is a transcription regulator for multiple cellular processes that is currently being tested as a potential target in several cancer types. PRMT5 has been previously shown to be overexpressed in approximately 75% of CRC patient tumor samples, as well as negatively correlated with CRC patient survival. Here, we provide evidence that PRMT5 can act as a surrogate target for mutated KRAS in CRC. Our findings show that PRMT5 expression is upregulated, as well as positively correlated with KRAS expression, in CRC patient datasets. Moreover, our results reveal that PRMT5 is further overexpressed in KRAS mutant CRC cells when compared to KRAS wild type (WT) CRC cells at both the transcriptional and translational levels. Additionally, our data demonstrate that this further overexpression of PRMT5 in the KRAS mutant CRC cells affects an even greater degree of growth inhibition, apoptosis, and cell cycle arrest, following treatment with PRMT5 inhibitor, when compared to the KRAS WT CRC cells. Our research therefore suggests for the first time that PRMT5 and KRAS may crosstalk, and thus, PRMT5 can potentially be used as a surrogate target for mutated KRAS in CRC.
KW - Arginine methylation
KW - CRC
KW - EPZ015666
KW - KRAS
KW - PRMT5
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U2 - 10.3390/cancers12082091
DO - 10.3390/cancers12082091
M3 - Article
AN - SCOPUS:85089202875
VL - 12
SP - 1
EP - 17
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 8
M1 - 2091
ER -