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Aberrant Bcl-x splicing in cancer: from molecular mechanism to therapeutic modulation

Zhihui Dou1,2,3,4, Dapeng Zhao1,2,3,4, Xiaohua Chen1,2,3,4

  • 1Department of Heavy Ion Radiation Medicine, Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China.

Journal of Experimental & Clinical Cancer Research : CR
|June 13, 2021
PubMed

Insights

Aberrant splicing of Bcl-x (B-cell lymphoma extra-large) pre-mRNA disrupts cell death regulation, contributing to cancer. Targeting Bcl-x splicing offers a promising strategy for novel cancer therapies.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Alternative splicing of Bcl-x pre-mRNA is crucial for regulating apoptosis and cell death.
  • Dysregulation of Bcl-x apoptotic isoforms through splicing errors is linked to human diseases, particularly cancers.
  • Understanding Bcl-x splicing mechanisms is key to developing cancer therapeutics that enhance cancer cell death.

Purpose of the Study:

  • To review the diverse splicing patterns and structural features of Bcl-x.
  • To outline the cis-regulatory elements, trans-acting factors, and epigenetic modifications governing Bcl-x splicing.
  • To highlight the role of aberrant Bcl-x splicing in cancer progression and therapeutic resistance.

Main Methods:

  • Literature review of Bcl-x splicing patterns and regulatory mechanisms.
  • Analysis of cis-regulatory elements and trans-acting factors influencing Bcl-x splicing.
  • Examination of epigenetic modifications affecting Bcl-x splicing.
  • Review of clinical strategies targeting Bcl-x splicing for cancer therapy.

Main Results:

  • Bcl-x exhibits multiple splicing patterns impacting apoptosis.
  • Aberrant Bcl-x splicing is implicated in cancer's evasion of apoptosis, autophagy, metastasis, and therapy resistance.
  • Clinical approaches like splice-switching oligonucleotides, small molecular modulators, and BH3 mimetics show potential for targeting Bcl-x splicing.

Conclusions:

  • Aberrant Bcl-x splicing isoforms represent significant therapeutic targets in human cancers.
  • Modulating Bcl-x splicing offers a viable strategy to sensitize cancer cells to death and overcome therapeutic resistance.
  • Targeting Bcl-x splicing holds promise for developing innovative cancer treatments.
Keywords:
Alternative splicingBcl-xCell apoptosisSmall molecular modulatorsSplice-switching oligonucleotidesSplicing correction

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