Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota.

Restriction of methionine (MR), a sulfur-containing essential amino acid, has been reported to repress cancer growth and improve therapeutic responses in several preclinical settings. However, how MR impacts cancer progression in the context of the intact immune system is unknown. Here we report that while inhibiting cancer growth in immunocompromised mice, MR reduces T cell abundance, exacerbates tumour growth and impairs tumour response to immunotherapy in immunocompetent male and female mice. Mechanistically, MR reduces microbial production of hydrogen sulfide, which is critical for immune cell survival/activation. Dietary supplementation of a hydrogen sulfide donor or a precursor, or methionine, stimulates antitumour immunity and suppresses tumour progression. Our findings reveal an unexpected negative interaction between MR, sulfur deficiency and antitumour immunity and further uncover a vital role of gut microbiota in mediating this interaction. Our study suggests that any possible anticancer benefits of MR require careful consideration of both the microbiota and the immune system.

Trending topics of SIRT1 in tumorigenicity.

BACKGROUND: Carcinogenesis is governed by a series of genetic alterations and epigenetic changes that lead to aberrant patterns in neoplastic cells. Sirtuin-1(SIRT1), an NAD+-dependent protein deacetylase, is capable of deacetylating histones and non-histone substrates that regulate various physiological activities during tumorigenesis. Recent studies have identified the role of SIRT1 in different stages of cancer, including genome instability, tumor initiation, proliferation, metabolism, and therapeutic response. However, the action of SIRT1 has been reported to be both oncogenic and tumor suppressive during carcinogenesis. Consequently, the biological functions of SIRT1 in cancer remain controversial. SCOPE OF REVIEW: We highlight the most recent findings on SIRT1 in different stages of tumorigenesis, and update the current status of SIRT1 small molecule modulators in clinical application of cancer treatment. MAJOR CONCLUSION: By targeting both tumor suppressors and oncogenic proteins, SIRT1 has a bifunctional role at different stages of tumorigenesis. The impact of SIRT1 on tumorigenesis is also distinct at different stages and is dependent on its dosages. SIRT1 suppresses tumor initiation through its functions in promoting DNA repair, increasing genome stability, and inhibiting inflammation at the pre-cancer stage. However, SIRT1 enhances tumor proliferation, survival, and drug resistance through its roles in anti-apoptosis, pro-tumor metabolism, and anti-inflammation (inhibition of anti-tumor immunity) at the stages of tumor progression, metastasis, and relapse. Consequently, both SIRT1 inhibitors and activators have been explored for cancer treatment. GENERAL SIGNIFICANCE: Better understanding the dose- and stage-dependent roles of SIRT1 in each cancer type can provide new avenues of exploration for therapy development.

CRISPR/Cas9-mediated Knockout of SIRT6 Imparts Remarkable Antiproliferative Response in Human Melanoma Cells in vitro and in vivo.

Melanoma is one of the most aggressive, potentially fatal forms of skin cancer and has been shown to be associated with solar ultraviolet radiation-dependent initiation and progression. Despite remarkable recent advances with targeted and immune therapeutics, lasting and recurrence-free survival remain significant concerns. Therefore, additional novel mechanism-based approaches are needed for effective melanoma management. The sirtuin SIRT6 appears to have a pro-proliferative function in melanocytic cells. In this study, we determined the effects of genetic manipulation of SIRT6 in human melanoma cells, in vitro and in vivo. Our data demonstrated that CRISPR/Cas9-mediated knockout (KO) of SIRT6 in A375 melanoma cells resulted in a significant (1) decrease in growth, viability and clonogenic survival and (2) induction of G1-phase cell cycle arrest. Further, employing a RT2 Profiler PCR array containing 84 key transformation and tumorigenesis genes, we found that SIRT6 KO resulted in modulation of genes involved in angiogenesis, apoptosis, cellular senescence, epithelial-to-mesenchymal transition, hypoxia signaling and telomere maintenance. Finally, we found significantly decreased tumorigenicity of SIRT6 KO A375 cells in athymic nude mice. Our data provide strong evidence that SIRT6 promotes melanoma cell survival, both in vitro and in vivo, and could be exploited as a target for melanoma management.

The sirtuin 6: An overture in skin cancer.

In the recent past, the sirtuins have been under intense investigation for their roles in biology and disease, including cancer. The sirtuin SIRT6 is comparatively a lesser studied member of this family of seven proteins. Like certain other sirtuins, SIRT6 is emerging to have an oncogenic function as well as tumor suppressor roles in cancer. Limited studies have been conducted assessing the role and functional significance of SIRT6 in melanoma and non-melanoma skin cancers. In this review, we have attempted to critically dissect the potential role and significance of SIRT6 in skin carcinogenesis. With limited available information to date, SIRT6 appears to have a pro-proliferative function in non-melanoma skin cancers (NMSCs), including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In addition, SIRT6 is also emerging to have an oncogenic function in melanoma. Moreover, we have provided information regarding the available SIRT6 inhibitors. Conclusively, it appears that additional comprehensive studies are needed to establish the role of SIRT6 in skin biology and skin diseases, including cancer. Further, concerted efforts are needed to characterize the stage-specific role of SIRT6 in skin cancers.