MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway

Abstract

The limited effectiveness of therapy for patients with advanced stage Head and Neck Squamous Cell Carcinoma (HNSCC) or recurrent disease is a reflection of an incomplete understanding of the molecular basis of HNSCC pathogenesis. MUC4, a high molecular weight glycoprotein, is differentially overexpressed in many human cancers and implicated in cancer progression and resistance to several chemotherapies. However its clinical relevance and the molecular mechanisms through which it mediates HNSCC progression are not well understood. The present study revealed a significant up-regulation of MUC4 in 78% (68/87) of HNSCC tissues compared to 10% (1/10) in benign samples [p= 0.006, OR (95% C.I) = 10.74 (2.0 - 57.56)]. MUC4 knockdown (KD) in SCC1 and SCC10B HNSCC cell lines resulted in significant inhibition of growth in vitro and in vivo, increased senescence as indicated by an increase in the number of flat, enlarged and senescence-associated β-galactosidase (SA-β-Gal) positive cells. Decreased cellular proliferation was associated with G0/G1 cell cycle arrest and decrease expression of cell cycle regulatory proteins like cyclin E, cyclin D1 and decrease in BrdU incorporation. Mechanistic studies revealed upregulation of p16, pRb dephosphorylation and its interaction with HDAC1/2. This resulted in decreased histone acetylation (H3K9) at Cyclin E promoter leading to its downregulation. Orthotropic implantation of MUC4 KD SCC1 cells into the floor of the mouth of nude mice resulted in the formation of significantly small tumors (170±18.30 mg) compared to bigger tumors (375 ±17.29 mg) formed by control cells (p= 0.00007). In conclusion, our findings showed that MUC4 overexpression plays a critical role by regulating proliferation and cellular senescence of HNSCC cells. Downregulation of MUC4 may be a promising therapeutic approach for treating HNSCC patients.

The cellular senescence of leukemia-initiating cells from acute lymphoblastic leukemia is postponed by β-Arrestin1 binding with P300-Sp1 to regulate hTERT transcription

“…P16 is involved in premature senescence as a tumor suppressor, 32 which is also involved in replicative senescence by the P16-RB pathway. 33 Thus, we explored the role of β -Arrestin1 on telomere-related replicative senescence, and found that β -Arrestin1 regulated the senescence via the hTERT -telomerase-telomere axis. However, the clear role of P16 gene on this process still need further study.…”

p16 expression in cutaneous squamous cell carcinoma of the head and neck is not associated with integration of high risk HPV DNA or prognosis

“…induction of p16 mRNA by microRNA (miR-877-3p) as shown in bladder carcinoma [19] ; as well as MUC4-modulated cellular senescence pathways, which have found to be p16dependent in HNSCC [20] . Furthermore, Nindl et al described higher frequency of mutations in CDKN2A in metastatic cSCCs as compared to primary tumours [8,15] .…”

YRNAs: New Insights and Potential Novel Approach in Head and Neck Squamous Cell Carcinoma

“…Finally, a gene set enrichment analysis showed that the high expression YRNA1 group was not enriched in any gene set, however, the low expression YRNA1 group was highly enriched in protein secretion processes, epidermal growth factor receptor binding, the RB-dependent pathway, the EIF4E-dependent pathway, the ERBB2-dependent pathway, the VEGF-dependent pathway, the EGFR-dependent pathway, and the cAMP-dependent pathway. These pathways are highly correlated with processes that occur during cancer development, such as enhanced proliferation, differentiation, and angiogenesis [22][23][24][25][26]. Moreover, the enhanced EIF4E-dependent pathway, which is responsible for translation initiation, was previously indicated to be overexpressed in the FaDu cell line, which is known to be the most aggressive HNSCC cell line [17].…”