MicroRNA-16 mediates the regulation of a senescence–apoptosis switch in cutaneous T-cell and other non-Hodgkin lymphomas

Abstract

Multiple sequential genetic and epigenetic alterations underlie cancer development and progression. Overcoming cellular senescence is an early step in cancer pathogenesis. Here, we demonstrate that a noncoding regulatory RNA, microRNA-16 (miR-16), has the potential to induce cellular senescence. First, we examined the expression of miR-16 in primary cutaneous T-cell lymphoma (CTCL) and other non-Hodgkin T/natural killer (NK)-cell lymphomas and found that miR-16 was downregulated than that in the corresponding normal cells. Notably, miR-16 expression was reduced as the primary CTCL progressed from the early stage to the advanced stage. Next, we transduced CTCL cells with miR-16 to examine whether this miRNA exhibited tumor-suppressive effects in CTCL cells. In CTCL cells expressing wild-type p53, forced expression of miR-16 enhanced p21 expression via downregulation of the polycomb group protein Bmi1, thereby inducing cellular senescence. Alternatively, in CTCL cells lacking functional p53, miR-16 induced compensatory apoptosis. The miR-16 transfection significantly decreased senescent cells and increased apoptotic cells in p21-knockdown CTCL cells expressing wild-type p53, suggesting that the presence or absence of p21 may be the most important condition in the senescence-apoptosis switch in CTCL lymphomagenesis. Furthermore, we found that the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) restored the expression of miR-16 and its essential targets, induced senescence in CTCL cells expressing wild-type p53 and promoted apoptosis in cells with nonfunctional p53. Moreover, we found that other T/NK-cell lymphoma cell lines showed similar tumor-suppressive effects in response to miR-16 and SAHA and that these effects were dependent on p53 status. These results suggested that epigenetic silencing of miR-16 may be a key step during lymphoma development. Elucidation of the essential targets of miR-16 and SAHA provides a basis for the clinical application of SAHA in the treatment of CTCL and other non-Hodgkin T/NK-cell lymphomas.

Histone deacetylase inhibitors inhibit metastasis by restoring a tumor suppressive microRNA-150 in advanced cutaneous T-cell lymphoma

“…Tissue samples were obtained from the metastatic lymph nodes of primary cases. Among the four CTCL cell lines, we previously demonstrated that the subcutaneous injection of My-La, HH, and HUT78 into NOD/Shi-scid IL-2γnul mice induced multiple metastases in various visceral organs [10, 11, 18]. Here, we confirmed there was an increased expression of HDACs (1, 2, 3, 4, and 6) and CCR6 in the CTCL cell lines and primary tissue samples (Figure 1A).…”

“…Along with inhibition of cell proliferation, miR-16 induced apoptosis or cellular senescence [18]. In this study, we also demonstrated that the induction of apoptosis or senescence was dependent on p53 status: miR-16 induced apoptosis in p53-mutated CTCL, but senescence in the p53 wild-type.…”

“…We previously established a mouse model of metastasis and invasion of CTCL in NOD/Shi-scid IL-2γnul (NOG) mice, which were transplantated with 2 × 105 My-La cells and died owing to tumor cell invasion and metastasis to multiple visceral organs/tissues during day 29–35 after the transplantation [10, 11, 18]. We used this in vivo mouse model to further determine whether miR-150 inhibits tumor metastasis.…”

“…Furthermore, vorinostat is known to induce apoptosis and growth inhibition of CTCL cells [15–18]. We also demonstrated that vorinostat induced cellular senescence in CTCL cells and other non-Hodgkin's lymphoma cell lines [18]. Another pan-HDACI, panobinostat, also has been recently approved by the FDA for refractory multiple myeloma [19].…”

Gene Expression Analysis Reveals Novel Gene Signatures Between Young and Old Adults in Human Prefrontal Cortex

“…In addition, miR-15b was a negative regulator of stress-induced SIRT4 expression thereby counteracting senescence associated mitochondrial dysfunction and regulating the senescence-associated secretory phenotype (SASP) and possibly organ aging, such as photoaging of human skin (Lang et al, 2016). Another study had shown forced expression of miR-16 could enhance p21 expression via down-regulation of the polycomb group protein Bmi1, thereby inducing cellular senescence (Kitadate et al, 2016). However, There were still no evidences whether the expression of hsa-miR-16-5p, hsa-miR-26b-5p, hsa-miR-15b-5p, hsa-miR-15a-5p changed with human brain aging.…”