Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia

Abstract

Splicing alterations are common in diseases such as cancer, where mutations in splicing factor genes are frequently responsible for aberrant splicing. Here we present an alternative mechanism for splicing regulation in T-cell acute lymphoblastic leukemia (T-ALL) that involves posttranslational stabilization of the splicing machinery via deubiquitination. We demonstrate there are extensive exon skipping changes in disease, affecting proteasomal subunits, cell-cycle regulators, and the RNA machinery. We present that the serine/arginine-rich splicing factors (SRSF), controlling exon skipping, are critical for leukemia cell survival. The ubiquitin-specific peptidase 7 (USP7) regulates SRSF6 protein levels via active deubiquitination, and USP7 inhibition alters the exon skipping pattern and blocks T-ALL growth. The splicing inhibitor H3B-8800 affects splicing of proteasomal transcripts and proteasome activity and acts synergistically with proteasome inhibitors in inhibiting T-ALL growth. Our study provides the proof-of-principle for regulation of splicing factors via deubiquitination and suggests new therapeutic modalities in T-ALL. SignifiCAnCE: Our study provides a new proof-of-principle for posttranslational regulation of splicing factors independently of mutations in aggressive T-cell leukemia. It further suggests a new drug combination of splicing and proteasomal inhibitors, a concept that might apply to other diseases with or without mutations affecting the splicing machinery.

Splicing Anomalies in Myeloproliferative Neoplasms: Paving the Way for New Therapeutic Venues

“…SRSF6 ubiquitination is deficient in T-ALL, resulting in altered exon inclusion, mainly affecting proteins with proteasomal function, or involved in RNA metabolism or cell cycle regulation. Spliceosome inhibitor (H3B-8800) showed synergistic effects with proteasome inhibitors in killing T-ALL cells [ 149 ].…”

CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer

“…So, splicing factors have been confirmed as oncogenic or suppressive drivers in multiple malignant tumors [ 10 , 11 ]. It is predicted that more than 90% of transcripts from interethnic protein-coding transcripts could be spliced alternatively in a tissue, under stress or in disease [ 12 ]. While the average human gene just produces three or more alternatively spliced mRNA isoforms, the tumor cells produce a significant redundant of splice variants [ 13 , 14 ].…”

Oncogenic lncRNA ZNF561-AS1 is essential for colorectal cancer proliferation and survival through regulation of miR-26a-3p/miR-128-5p-SRSF6 axis

“…SRSF6 is a proto-oncogene often overexpressed in human skin cancer [ 27 ]. By controlling exon skipping, SRSF6 is critical for leukemia cells survival [ 28 ]. SRSF6 is also overexpressed in CRC [ 29 ].…”