Biology subjects

Alkallas, R.

Publications and source records attributed to Alkallas, R..

3 recordsLinked to original sources

bioRxiv2026

A map of RBP-miRNA regulatory connections for deciphering the mechanisms of transcriptome remodeling in cancer

Micro-RNAs (miRNAs) are key post-transcriptional regulators of gene expression that influence cancer progression and outcome. Whereas transcriptional dysregulation of miRNA abundance underlies abnormal functionality of some miRNAs in cancer, emerging data points to RNA-binding proteins (RBPs) as prominent post-transcriptional regulators of miRNA activity. Here, by modelling the regulon activities of well-characterized miRNA families in RNA-seq data of a comprehensive collection of RBP inhibition experiments, human cell lines and tissues, we report a map of regulatory connections between 34 RBPs and 28 miRNAs. Furthermore, through a global analysis of the abundance as well as the activity of miRNAs in thousands of tumor and control samples from 17 human cancers, we show that RBP-driven regulation of miRNA activity is common in tumors and contributes to the heterogeneity in miRNA activity profiles. We uncover a set of RBPs that regulate the activity of tumor-suppressor and oncogenic miRNAs, including miR-29-3p, miR-17-5p and miR-19-3p. Of particular interest, we describe a pan-cancer negative regulatory role for DDX55 on the activity of the miR-29-3p family, a critical miRNA family with tumor suppressor functions that is involved in most human cancers. Our functional studies confirm that DDX55 inhibition restores the gene-silencing activity of miR-29-3p and reduces cancer cell viability. Overall, our study provides the first pan-cancer investigation of functional regulatory connections between RBPs and miRNAs, and highlights RBPs whose interventional modulation may serve as a new approach to reprogram abnormal miRNA activities in cancer.

genomics↗

bioRxiv2021

A nuclear cAMP microdomain suppresses tumor growth by Hippo pathway inactivation

cAMP signaling pathways are critical for both oncogenesis and tumor suppression. cAMP signaling is localized to multiple spatially distinct microdomains, but the role of cAMP microdomains in cancer cell biology is poorly understood. We developed a tunable genetic system that allows us to activate cAMP signaling in specific microdomains. We uncovered a previously unappreciated nuclear cAMP microdomain that functionally activates a tumor suppressive pathway in a broad range of cancers by inhibiting YAP, a key effector protein of the Hippo pathway, inside the nucleus. We show that nuclear cAMP induces a LATS-dependent pathway leading to phosphorylation of nuclear YAP solely at serine 397, export of YAP from the nucleus, without YAP protein degradation. Thus, nuclear cAMP inhibition of nuclear YAP is distinct from other known mechanisms of Hippo regulation. Pharmacologic targeting of specific cAMP microdomains remains an untapped therapeutic approach for cancer, and since Hippo pathway deregulation can lead to oncogenesis and chemotherapeutic resistance, drugs directed at the nuclear cAMP microdomain may provide new avenues for the treatment of cancer.

cancer biology↗

bioRxiv2021

Pan-cancer analysis of mRNA stability for decoding tumour post-transcriptional programs

RNA stability is a crucial and often overlooked determinant of gene expression. Some of the regulators of mRNA stability are long known as key oncogenic or tumour suppressor factors. Nonetheless, the extent to which mRNA stability contributes to transcriptome remodeling in cancer is unknown, and the factors that modulate mRNA stability during cancer development and progression are largely uncharacterized. Here, by decoupling transcriptional and post-transcriptional effects in RNA-seq data of 7760 samples from 18 cancer types, we present a pan-cancer view of the mRNA stability changes that accompany tumour development and progression. We show that thousands of genes are dysregulated at the mRNA stability level, and identify the potential factors that drive these changes, including >80 RNA-binding proteins (RBPs) and microRNAs (miRNAs). Most RBPs and miRNAs have cancer type-specific activities, but a few show recurrent inactivation across multiple cancers, including the RBFOX family of RBPs and miR-29. Analysis of cell lines with phenotypic activation or inhibition of RBFOX1 and miR-29 confirms their role in modulation of genes that are dysregulated across multiple cancers, with functions in calcium signaling, extracellular matrix organization, and stemness. Overall, our study highlights the critical role of mRNA stability in shaping the tumour transcriptome, with recurrent post-transcriptional changes that are ~30% as frequent as transcriptional events. These results provide a resource for systematic interrogation of cancer-associated stability drivers and pathways.

genomics↗