Sirt5 is dispensable for Braf^V600E‐mediated cutaneous melanoma development and growth in vivo

Abstract

Sirt5 is known to functionally regulate mitochondrial proteins by altering posttranslational modifications, including lysine desuccinylation. While roles for Sirt5 as either a tumor promoter or suppressor, or in chemoresistance, have been implicated in other cancers, the function of Sirt5 in cutaneous melanoma has not been well examined. Therefore, to determine whether Sirt5 is necessary for BrafV600E‐mediated melanoma formation and/or disease progression, we crossed a genetically engineered murine melanoma model (TyrCreERT2/+; BrafLSL‐V600E/+; Ptenflox/flox) to Sirt5−/− knockout animals. In addition, we tested for synergism with a selective BRAF (V600E) inhibitor in Sirt5−/− mouse melanoma cells. Taken together, this report demonstrates that, in these models, Sirt5 is dispensable for BrafV600E‐mediated cutaneous melanoma formation and growth in vivo, and does not improve sensitivity to a selective BRAF inhibitor.

SIRT5 Promotes Cisplatin Resistance in Ovarian Cancer by Suppressing DNA Damage in a ROS-Dependent Manner via Regulation of the Nrf2/HO-1 Pathway

“…In contrast, SIRT5 was found to inhibit gastric cancer cell proliferation and tumor formation by inhibiting aerobic glycolysis (36). Interestingly, SIRT5 is not necessary for BrafV600E-mediated cutaneous melanoma initiation and growth in vivo (37). With respect to its function in chemoresistance, SIRT5 knockdown sensitizes NSCLC A549 cells to multiple chemotherapeutics including cisplatin (13).…”

The sirtuin 6: An overture in skin cancer

“…[59] In contrast to SIRT6, sirtuin 5 (SIRT5) does not improve sensitivity to BRAF inhibitors in BRAF V600 -mutant melanoma animals. [59,60] Given the targetable properties of SIRT6 in melanoma and non-melanoma skin cancers, the development of SIRT6-specific inhibitors accompanied by detailed molecular insights into the mechanistic and therapeutic tangibility of SIRT6 in skin is essential for the development of novel strategies to modulate skin cancer. [59]…”

“…This study identified not only an epigenetic mechanism of drug resistance, but also provided a rationale for a new combination therapy that could overcome resistance to standard‐of‐care therapy for BRAF V600 ‐mutant melanoma patients . In contrast to SIRT6, sirtuin 5 (SIRT5) does not improve sensitivity to BRAF inhibitors in BRAF V600 ‐mutant melanoma animals . Given the targetable properties of SIRT6 in melanoma and non‐melanoma skin cancers, the development of SIRT6‐specific inhibitors accompanied by detailed molecular insights into the mechanistic and therapeutic tangibility of SIRT6 in skin is essential for the development of novel strategies to modulate skin cancer …”

Combined Inhibition of Specific Sirtuins as a Potential Strategy to Inhibit Melanoma Growth

“…The role of SIRT4 and SIRT7 in melanoma have not been explored. SIRT5 has been shown to be dispensable for BRAF V600E -mediated melanoma development and also does not affect sensitivity to a selective BRAF inhibitor (16). Similar to SIRT1 and SIRT3, SIRT6 has been shown to possess a pro-proliferative role in melanoma (17)(18)(19).…”