PABPN1 regulates mRNA alternative polyadenylation to inhibit bladder cancer progression
Liang Chen1, Wei Dong1, Menghao Zhou1
1Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Background:
About 10-20% of patients with bladder cancer (BC) progress to muscle-invasive diseases, of which the underlying key molecular events have yet to be addressed.
Results:
Here, we identified poly(A) binding protein nuclear 1 (PABPN1), a general factor of alternative polyadenylation (APA), was downregulated in BC. Overexpression and knockdown of PABPN1 significantly decreased and increased BC aggressiveness, respectively. Mechanistically, we provide evidence that the preference of PABPN1-bound polyadenylation signals (PASs) depends on the relative location between canonical and non-canonical PASs. PABPN1 shapes inputs converging on Wnt signaling, cell cycle, and lipid biosynthesis.
Conclusions:
Together, these findings provide insights into how PABPN1-mediated APA regulation contributes to BC progression, and suggest that pharmacological targeting PABPN1 might have therapeutic potential in patients with BC.
Insights
Poly(A) binding protein nuclear 1 (PABPN1) downregulation promotes bladder cancer (BC) progression by altering alternative polyadenylation. Targeting PABPN1 may offer new therapeutic strategies for BC patients.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Bladder cancer (BC) progression to muscle-invasive disease involves key molecular events that remain largely uncharacterized.
- Approximately 10-20% of BC patients develop muscle-invasive disease, highlighting an unmet need for understanding its progression.
Purpose of the Study:
- To investigate the role of poly(A) binding protein nuclear 1 (PABPN1) in bladder cancer (BC) progression.
- To elucidate the molecular mechanisms by which PABPN1 influences BC aggressiveness and alternative polyadenylation (APA).
Main Methods:
- Investigated PABPN1 expression levels in bladder cancer.
- Utilized overexpression and knockdown techniques to assess PABPN1's impact on BC cell behavior.
- Analyzed PABPN1's binding preferences to polyadenylation signals (PASs) and its downstream effects on signaling pathways.
Main Results:
- PABPN1 was found to be downregulated in bladder cancer.
- PABPN1 overexpression decreased BC aggressiveness, while its knockdown increased it.
- PABPN1 regulates APA by influencing the choice of polyadenylation signals (PASs), impacting Wnt signaling, cell cycle, and lipid biosynthesis pathways.
Conclusions:
- PABPN1-mediated alternative polyadenylation (APA) plays a significant role in bladder cancer (BC) progression.
- PABPN1 downregulation contributes to BC aggressiveness.
- Pharmacological targeting of PABPN1 presents a potential therapeutic avenue for bladder cancer (BC).
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