Biology subjects

Chan, T. H. M.

Publications and source records attributed to Chan, T. H. M..

2 recordsLinked to original sources

bioRxiv2021

ADAR2-repressed RNA editing: a novel mechanism contributing to t (8:21) AML leukemogenesis

In the past decade, adenosine to inosine (A-to-I) RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes ADAR1 and ADAR2, has been shown to contribute to the development and progression of multiple cancers; however, very little is known about its role in acute myeloid leukemia (AML) - the second most common type of leukemia making up 31% of all adult leukemia cases. Here, we found that ADAR2, but not ADAR1 and ADAR3, is specifically downregulated in core binding factor (CBF) AML with t(8;21) or inv(16). In t(8;21) AML, RUNX1-driven transcription of ADAR2 transcripts was found to be repressed by the RUNX1-ETO fusion protein. Forced overexpression of two ADAR2-regulated RNA editing targets COPA and COG3 indeed inhibits clonogenic growth of human t(8;21) AML cells. Further in vivo animal studies confirmed that ADAR2 could suppress leukemogenesis of t(8;21) AML through its RNA binding and editing capabilities. Our results suggest a novel RNA editing-mediated mechanism leading to t(8,12) AML. Key pointsO_LIADAR2, but not ADAR1 and ADAR3, was specifically downregulated in CBF-AML C_LIO_LIRUNX1-ETO suppresses ADAR2 transcription in t(8;21) AML through binding on its promoter C_LIO_LIRNA editing capability of ADAR2 is essential for its repression of leukemogenesis in an AE9a mouse model C_LI

cancer biology↗

bioRxiv2020

HNRNPM controls circRNA biogenesis and splicing fidelity to sustain prostate cancer cell fitness

Cancer cells are differentially dependent on the splicing machinery compared to normal untransformed cells. The splicing machinery thus represents a potential therapeutic target in cancer. To identify splicing factors important for prostate cancer cell (PCa) cell growth, we performed a parallel pooled shRNA screen on in vitro passaged cells and in vivo xenografted PCa tumor lines. Our screen revealed HNRNPM as a potential regulator of PCa cell growth. RNA- and eCLIP-sequencing data suggest that HNRNPM is bound to transcripts of key homeostatic genes and that loss of HNRNPM binding in a subset of these genes results in aberrant exon inclusion and exon back-splicing events in target transcripts. In both linear and circular mis-spliced transcripts, HNRNPM appears to preferentially bind to GU-rich elements in long flanking proximal introns. Mimicry of HNRNPM dependent linear splicing events using splice-switching antisense oligonucleotides (SSOs) was sufficient to inhibit cell growth in HNRNPM expressing cells. This suggests that prostate cancer cell dependence on HNRNPM is likely a result of mis-splicing of key homeostatic coding and non-coding genes. Taken together, our data reveal a role for HNRNPM in supporting prostate cancer cell fitness, and also as a potential therapeutic target in PCa.

genomics↗